Preparation method of 2, 3, 4, 6-tetra-O-trimethylsilyl-D-glucolactone
By using low boiling point aprotic solvent and reduced pressure reflux technology in the preparation of 2,3,4,6-tetramethylsilicone-D-gluconate lactone, the problems of incomplete silicon protection and by-product generation in the existing methods are solved, and high purity and high yield preparation is achieved, and simple operation and environmentally friendly.
Patent Information
- Application Number
- CN202510355904.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-25
- Publication Date
- 2025-06-27
AI Technical Summary
In the existing preparation method of 2,3,4,6-tetramethylsilyl-D-gluconic acid lactone, it is difficult to achieve complete silicon protection, resulting in impurities generation, affecting the purity and yield of the product. At the same time, there are problems with by-product hydrogen chloride and waste salt, which increases production costs and environmental pressure.
The silanization reaction is carried out by using a low-boiling point aprotic solvent combined with a reduced pressure reflux technology. The reaction steps and post-treatment flow are simplified by removing the hydrogen chloride tail gas and avoiding the use of acid binding agents and catalysts.
The reaction time is greatly shortened, the yield and purity of the product is improved, energy consumption and production costs are reduced, by-products and waste salt are avoided, and a green and environmentally friendly preparation method is realized.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of chemical synthesis, and particularly relates to a preparation method of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone. Background Art
[0002] The molecular formula of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (2,3,4,6-Tetrakis-O-trimethylsilyl-D-gluconolactone, Compound I) is C 18 H 42 O6Si4, also known as the intermediate of dapagliflozin, is a key starting material for the preparation of SGLT-2 inhibitors (such as canagliflozin, dapagliflozin, and empagliflozin, etc.) for the treatment of type II diabetes in adult patients, and has very wide applications.
[0003] The currently commonly used preparation method of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone is to slowly drop trimethylchlorosilane (TMSCl) into a reaction system containing tetrahydrofuran and N-methylmorpholine (NMM, an acid-binding agent). After the dropping is completed, gluconolactone (Compound II) is added, and then 4-dimethylaminopyridine is added to promote the silylation reaction, and finally 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone is obtained (see Formula 1).
[0004]
[0005] Formula 1 However, the above preparation method has the following problems: Compound I contains four hydroxyl groups and needs to be protected with silicon. Usually, it is difficult to achieve complete silicon protection for the last remaining hydroxyl group, which results in the formation of impurities with incomplete silicon protection, thus affecting the purity of the product. Since the formation of by-product hydrogen chloride occurs during the silylation protection, in order to ensure the smooth progress of the silylation reaction, an appropriate amount of acid-binding agent must be added to neutralize the by-product hydrogen chloride. Glucono-δ-lactone is very likely to form five-membered ring impurities (Compound III) under alkaline conditions and will further react to become five-membered ring impurities (Compound IV) after the dropwise addition of trimethylchlorosilane (see Equation 2), significantly reducing the yield and purity of Compound I, and the highest GC purity is only 98.7%. Given that the heat released during the reaction of trimethylchlorosilane with N-methylmorpholine is quite intense, during the dropwise addition of trimethylchlorosilane, the solvent system must be cooled to -5°C to 15°C and trimethylchlorosilane should be added dropwise slowly to prevent the reaction from being too intense. In addition, the salts formed by the reaction of the acid-binding agent with the by-product hydrogen chloride are insoluble in the reaction system, resulting in a solid-liquid mixed state of the system. This not only hinders the smooth progress of the silylation reaction but also may adsorb the product, thereby reducing the yield. At the same time, the treatment of these waste salts increases the complexity of the post-treatment and causes greater pressure on the environment.
[0006]
[0007] Equation 2 Currently, there is no public report on the research of the above problems. Therefore, it is urgent to develop a method for preparing 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone with simple operation, environmental friendliness, high purity and high yield. Summary of the Invention
[0008] In view of the above problems, the present invention provides a method for preparing 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone. By adopting a low-boiling aprotic solvent combined with a reduced-pressure reflux technique, it is beneficial to the progress of the silylation reaction, significantly shortening the reaction time, improving the yield and purity of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone, and having simple operation and environmental friendliness.
[0009] To solve the above technical problems, the technical solution provided by the present invention is as follows: A method for preparing 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone, comprising the following steps: Add D-glucono-δ-lactone and trimethylchlorosilane to a low-boiling aprotic solvent, and carry out a reduced-pressure reflux reaction at 30°C to 40°C to obtain 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone.
[0010] Compared with the prior art, the preparation method of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone provided by the present invention uses a reduced-pressure reflux technique for the silylation reaction, takes the hydrogen chloride tail gas away from the reaction system, and combines the use of a low-boiling aprotic solvent, effectively increasing the concentration of the reaction system. This improvement is beneficial to the progress of the silylation reaction and greatly shortens the reaction time. In addition, this preparation method avoids the use of catalysts (such as 4-dimethylaminopyridine DMAP), thereby further reducing the production cost. The present invention does not use an acid-binding agent (such as NMM), eliminates the exothermic risk when introducing trimethylchlorosilane, does not require additional cooling measures, effectively reduces energy consumption, and also avoids the generation of by-product waste salts, eliminating the operation process of separating waste salts, achieving resource conservation and environmental protection, and having good market application value.
[0011] Through a large number of experiments, the present invention finds that if the temperature of the reduced-pressure reflux reaction is lower than 30 °C, the reflux reaction is not easy to proceed, and the hydrogen chloride gas is not easily carried out of the reaction system; if the temperature of the reduced-pressure reflux reaction is too high, a large number of side reactions will occur in the reaction, increasing the content of impurities, which has no impact on the yield and purity of the final product.
[0012] Preferably, the molar ratio of D-glucono-δ-lactone to trimethylchlorosilane is 1:(4.1~4.3).
[0013] Preferably, the addition temperature of trimethylchlorosilane is 20 °C~30 °C.
[0014] The present invention adds trimethylchlorosilane at room temperature, which can control the impurity content in the reaction system within a lower range and control the risk of heat release during the silylation reaction, without the need for additional cooling measures (such as -5 °C~15 °C), effectively reducing energy consumption.
[0015] Preferably, the low-boiling aprotic solvent includes at least one of dichloromethane or chloroform.
[0016] Preferably, the mass-volume ratio of D-glucono-δ-lactone to the low-boiling aprotic solvent is 1 g:(1~3) mL.
[0017] Preferably, the pressure of the reduced-pressure reflux reaction is -0.08 MPa~-0.1 MPa, and the reaction time is 4 h~6 h.
[0018] By controlling the conditions of the reduced-pressure reflux reaction, the present invention can better reuse low-boiling-point aprotic solvents, significantly reducing the preparation cost. In combination with a specific low-boiling-point aprotic solvent, the time of the silylation reaction is shortened from 18 h in the prior art to 4 h - 6 h, greatly improving the reaction efficiency and significantly saving the production cost. In addition, an aqueous hydrochloric acid solution can be obtained, realizing the recycling and reuse of hydrogen chloride tail gas and further reducing the production cost.
[0019] Preferably, after the reduced-pressure reflux reaction, the following post-treatment steps are further included: The obtained reaction system is quenched with water, phase-separated, and the organic phase is taken for reduced-pressure concentration to obtain 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone.
[0020] The preparation method of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone provided by the present invention simplifies the post-treatment process, is easy to operate and has no environmental burden. The post-treatment only needs to be completed through the steps of quenching with water, phase-separating and concentration, omitting the steps of using an aqueous solution of sodium dihydrogen phosphate to neutralize the excess acid-binding agent and using basic aluminum oxide to adsorb impurities in the organic phase, so as not to cause damage to the environment caused by waste basic aluminum oxide solids.
[0021] More preferably, the volume ratio of the water to the low-boiling-point aprotic solvent is 1:(1 - 3).
[0022] More preferably, the temperature of the quenching is -5°C to 10°C.
[0023] Exemplarily, the phase separation is carried out by standing at room temperature.
[0024] More preferably, the temperature of the reduced-pressure concentration is 40°C to 50°C, the pressure is -0.08 MPa to -0.1 MPa, and the reduced-pressure concentration is carried out until the water content in the system is ≤0.05 wt%. Specific Embodiments
[0025] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.
[0026] In the present invention, unless otherwise specified, all materials are commercially available products.
[0027] Example 1 This example provides a preparation method of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone, including the following steps: S1, Add 100 mL of chloroform and 100 g (0.56 mol, 1.0 eq) of D-glucono-δ-lactone to the reaction kettle in sequence. At room temperature, add 251 g (2.31 mol, 4.1 eq) of trimethylchlorosilane dropwise. After the addition is complete, connect a serpentine condenser. The upper end of the condenser is connected to a tail gas recovery bottle for recovering the hydrochloric acid aqueous solution formed by hydrogen chloride gas. Carry out a reduced-pressure reflux reaction at 30 °C and -0.08 MPa. After 6 h, take a sample. The sum of the contents of impurities with RRT 0.96 and RRT 0.98 (RRT 0.96 and RRT 0.98 are impurities with one hydroxyl group not protected) is less than 1.0%, and the reaction ends; S2, Add 100 mL of water to the obtained reaction system at -5 °C for quenching. Let it stand for phase separation. Take the organic phase and carry out reduced-pressure concentration at 40 °C and -0.08 MPa. After 2 h, the water content of the system is 0.02 wt%. Obtain 259.46 g (0.56 mol) of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone, with a yield of 99.0% and a GC purity of 99.60%. The sum of the contents of impurities with RRT 0.96 and RRT 0.98 is 0.40%.
[0028] Example 2 This example provides a preparation method of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone, including the following steps: S1, Add 300 mL of dichloromethane and 100 g (0.56 mol, 1.0 eq) of D-glucono-δ-lactone to the reaction kettle in sequence. At room temperature, add 262 g (2.41 mol, 4.3 eq) of trimethylchlorosilane dropwise. After the addition is complete, connect a serpentine condenser. The upper end of the condenser is connected to a tail gas recovery bottle for recovering the hydrochloric acid aqueous solution formed by hydrogen chloride gas. Carry out a reduced-pressure reflux reaction at 40 °C and -0.1 MPa. After 4 h, take a sample. The sum of the contents of impurities with RRT 0.96 and RRT 0.98 is less than 1.0%, and the reaction ends; S2, Add 100 mL of water to the obtained reaction system at 10 °C for quenching. Let it stand for phase separation. Take the organic phase and carry out reduced-pressure concentration at 50 °C and -0.1 MPa. After 2 h, the water content of the system is 0.01 wt%. Obtain 260.25 g (0.56 mol) of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone, with a yield of 99.3% and a GC purity of 99.65%. The sum of the contents of impurities with RRT 0.96 and RRT 0.98 is 0.35%.
[0029] Example 3 This example provides a preparation method of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone, including the following steps: S1. Add 200 mL of dichloromethane and 100 g (0.56 mol, 1.0 eq) of D-glucono-δ-lactone into the reaction kettle in sequence. Flowingly add 255 g (2.35 mol, 4.2 eq) of trimethylchlorosilane at room temperature. After the dropping is completed, connect a snake-shaped condenser. The upper end of the condenser is connected to a tail gas recovery bottle for recovering the hydrochloric acid aqueous solution formed by hydrogen chloride gas. Carry out a reduced-pressure reflux reaction at 35 °C and -0.09 MPa. After 5 h, take a sample. The sum of the contents of impurities with RRT 0.96 and RRT 0.98 is less than 1.0%, and the reaction ends. S2. Add 100 mL of water to the obtained reaction system at 5 °C for quenching. Let it stand for phase separation. Take the organic phase and carry out reduced-pressure concentration at 45 °C and -0.09 MPa. After 2 h, the water content of the system is 0.02 wt%. Obtain 259.98 g (0.56 mol) of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone, with a yield of 99.2% and a GC purity of 99.61%. The sum of the contents of impurities with RRT 0.96 and RRT 0.98 is 0.39%.
[0030] Comparative Example 1 This comparative example provides a preparation method of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone (a conventional preparation method in the art), including the following steps: S1. Add 200 mL of tetrahydrofuran and 79.7 g (0.79 mol, 7.0 eq) of N-methylmorpholine into the reaction kettle in sequence. Flowingly add 73.3 g (0.67 mol, 6.0 eq) of trimethylchlorosilane at 20 °C. After the dropping is completed, add 20 g (0.11 mol, 1.0 eq) of D-glucono-δ-lactone in batches at 30 °C, and then add 0.27 g (2.21 mmol, 0.02 eq) of DMAP. React at 35 °C for 5 h, and then end the reaction. S2. Add 100 g of toluene and 25 mL of water to the obtained reaction system at 5 °C for quenching, and supplement 62.5 mL of water to make the system clear. Let it stand for phase separation. Extract the aqueous phase with 25 mL of toluene and combine the organic phases. Wash the organic phase with 135 g of 7% sodium dihydrogen phosphate aqueous solution and 130 g of saturated brine respectively, then pass through basic aluminum oxide and carry out reduced-pressure concentration at 40 °C to obtain 50.16 g (0.11 mol) of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone, with a yield of 95.7% and a GC purity of 98.30%. The sum of the contents of impurities with RRT 0.96 and RRT 0.98 is 1.54%, and the content of impurity compound IV is 0.16%.
[0031] Comparative Example 2 This comparative example provides a method for preparing 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone, which is similar to Example 1, except that: the silylation reaction is carried out at normal pressure of 40 °C (without decompression and without reflux). The specific steps are as follows: Add 100 mL of chloroform and 100 g (0.56 mol, 1.0 eq) of D-glucono-δ-lactone to the reaction kettle in sequence, add 251 g (2.31 mol, 4.1 eq) of trimethylchlorosilane dropwise at room temperature. After the addition is complete, react at 40 °C and normal pressure for 48 h. The GC purity is 53.37%, the reaction is incomplete, and the experiment is abandoned.
[0032] Comparative Example 3 This comparative example provides a method for preparing 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone, which is similar to Example 1, except that: replace chloroform with toluene and appropriately adjust the temperature and time of the vacuum reflux reaction. The specific steps are as follows: S1, Add 100 mL of toluene and 100 g (0.56 mol, 1.0 eq) of D-glucono-δ-lactone to the reaction kettle in sequence, add 251 g (2.31 mol, 4.1 eq) of trimethylchlorosilane dropwise at room temperature. After the addition is complete, connect a serpentine condenser. The upper end of the condenser is connected to a tail gas recovery bottle for recovering the hydrochloric acid aqueous solution formed by hydrogen chloride gas, and carry out a vacuum reflux reaction at 60 °C and -0.08 MPa. After 14 h, take a sample. The sum of the contents of impurities RRT0.96 and RRT0.98 is less than 1.0%, and the reaction ends; S2, Add 100 mL of water to the obtained reaction system at -5 °C for quenching, let it stand for phase separation, take the organic phase and carry out vacuum concentration at 40 °C and -0.08 MPa. After 2 h, the water content of the system is 0.02 wt%, and 250.81 g (0.54 mol) of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone is obtained. The yield is 95.7%, the GC purity is 92.79%, the sum of the contents of impurities RRT0.96 and RRT0.98 is 0.85%, and the content of impurity compound Ⅳ is 6.36%.
[0033] The products (2,3,4,6-tetra-O-trimethylsilyl-D-glucono-δ-lactone) prepared in Examples 1 to 3 and Comparative Examples 1 to 3 were respectively determined by gas chromatography (General Rules 0521, Volume IV, Chinese Pharmacopoeia 2020 Edition), and the test results are shown in Table 1.
[0034] Table 1 Gas Chromatography Test Results of Products in Examples and Comparative Examples
[0035] As can be seen from the table, the preparation method of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone provided by the embodiments of the present invention is simple in operation, has a relatively short overall reaction time, pollution-free post-treatment, low raw material cost, and the product yield is above 99%, and the purity is as high as above 99.5%. Compared with Embodiments 1 to 3, the post-treatment steps of Comparative Example 1 are numerous, the yield loss is large, and the raw material cost is high. The alkaline alumina waste solid will cause certain damage to the environment; in Comparative Example 2, hydrogen chloride is likely to generate side reactions with the raw materials, resulting in the consumption of raw materials and even the decomposition of the product, reducing the overall yield; in Comparative Example 3, the boiling point of the solvent toluene is high. In order to carry out the reaction under reduced pressure and reflux, the temperature needs to be raised above 60 °C. At this time, the by-product hydrogen chloride cannot be completely separated, affecting the progress of the reaction. Therefore, the reaction time is long and a large amount of Compound IV impurities are generated.
[0036] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, or improvements made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.
Claims
1. A method for preparing 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone, characterized in that: The following steps are involved: D-glucono-δ-lactone and trimethylsilyl chloride are added to a low-boiling-point aprotic solvent, and a reduced-pressure reflux reaction is carried out at 30° C. to 40° C. to obtain 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-lactone.
2. The method for preparing 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone according to claim 1, characterized in that: The molar ratio of the D-glucono-δ-lactone to trimethylchlorosilane is 1:(4.1-4.3).
3. The method for preparing 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone according to claim 1, characterized in that: The adding temperature of the trimethylsilyl chloride is 20°C to 30°C.
4. The method for preparing 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone according to claim 1, characterized in that: The low boiling point aprotic solvent includes at least one of dichloromethane or chloroform.
5. The method for preparing 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone according to claim 1 or 4, characterized in that, The mass volume ratio of the D-glucono-δ-lactone and the low-boiling-point aprotic solvent is 1 g: (1-3) mL.
6. The method for preparing 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone according to claim 1 or 4, characterized in that: The pressure of the reduced pressure reflux reaction is -0.08MPa~-0.1MPa, and the reaction time is 4h~6h.
7. The method for preparing 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone according to claim 1, characterized in that: After the reduced pressure reflux reaction is completed, the following post-processing steps are also included: The obtained reaction system was quenched by adding water, the phases were separated, and the organic phase was concentrated under reduced pressure to obtain 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone.
8. The method for preparing 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone according to claim 7, characterized in that: The volume ratio of the water to the low-boiling-point aprotic solvent is 1:(1-3).
9. The method for preparing 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone according to claim 7, characterized in that: The quenching temperature is -5°C to 10°C.
10. The method for preparing 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone according to claim 7, characterized in that: The temperature of the reduced pressure concentration is 40° C. to 50° C., the pressure is -0.08 MPa to -0.1 MPa, and the reduced pressure concentration is performed until the water content of the system is ≤0.05wt%.