A process for the synthesis of 2-chloro-5-(beta-d-glucopyranos-1-yl)-4'-ethoxydiphenylmethane green

Abstract

This invention discloses a green synthesis process for 2-chloropyranose-1-yl)-4'-ethoxydiphenylmethane, belonging to the field of pharmaceutical intermediate preparation. The method involves forming a mixture of a substrate in the protected state of Formula I and a reducing agent containing siloxane bonds, which is continuously fed into a microreactor loaded with a confined-domain MOF (Metal-Oxide-Fractions) supported catalyst for room-temperature reduction. The MOF catalyst has a rigid pore size of 1.2~2.5 nm and internally coordinates and anchors metal trifluoromethanesulfonate. This invention utilizes the limiting confinement effect of rigid channels to lock the substrate conformation, blocking the surface attack of reactants and achieving extremely high configuration selectivity. Simultaneously, the efficient mass transfer of the continuous flow microchannel and the online infrared spectroscopy closed-loop control system completely eliminate the need for traditional cryogenic conditions, remove highly corrosive fluorine-containing waste liquid, significantly reduce synthesis costs, and achieve efficient, green, and stable continuous industrial production of this core intermediate.

Description

Technical Field

[0001] This invention relates to a 2-chloro The green synthesis process of pyranose-1-yl)-4'-ethoxydiphenylmethane belongs to the field of pharmaceutical intermediate preparation. Background Technology

[0002] Dagglitazone is a highly potent sodium-glucose cotransporter 2 (SGLT2) inhibitor, widely used in the development of antidiabetic drugs. Its core structural backbone consists of a glucose ring and a diphenylmethane fragment via... The configuration involves carbon-carbon bond connections. In existing classical synthetic routes, the protecting group derivative of 1-C-[4-chloro-3-(4-ethoxybenzyl)phenyl]-D-pyranose gluconate hemiacetal is reduced to... The configuration C-glycoside is the rate-limiting and cost-controlling step in the entire process.

[0003] Currently, batch reactors are commonly used in industry, with boron trifluoride ether as a homogeneous Lewis acid and triethylsilane as a reducing agent for this reduction step.

[0004] However, this existing technology is extremely energy-intensive and difficult to scale up. The reaction process is highly exothermic, and the intermediates are reactive. Industrial scale-up requires strict reliance on ultra-low temperature cryogenic equipment at -78°C, resulting in extremely high operating costs and safety hazards. The catalyst, boron trifluoride diethyl ether, is highly corrosive, requiring large-scale quenching with alkaline solution after the reaction, generating large quantities of difficult-to-treat industrial wastewater containing fluorine, boron, and aluminum. The reducing agent, triethylsilane, is a fine reducing agent, and its bulk procurement cost significantly increases the overall material cost of the active pharmaceutical ingredient. The heat and mass transfer efficiency of batch reactor reactions is limited by the stirring system, and localized temperature rises can easily lead to thermodynamically difficult-to-separate reactions. Increased impurities in isomers make it difficult to meet the quality requirements for high-purity active pharmaceutical ingredients.

[0005] Therefore, there is an urgent need to find an environmentally friendly and easy-to-operate efficient synthesis method. Summary of the Invention

[0006] The purpose of this invention is to provide a 2-chloro The green synthesis process of pyranose-1-yl)-4'-ethoxydiphenylmethane aims to overcome the shortcomings of existing technologies, get rid of the ultra-low temperature cryogenic environment, eliminate fluorine- and boron-containing waste liquids, and reduce the cost of reducing agents.

[0007] The objective of this invention is achieved through the following technical solution: a 2-chloro A green synthesis process for pyranose-1-yl)-4'-ethoxydiphenylmethane, using compound I as a reaction substrate to prepare compound II, includes the following steps: S1: Dissolve the compound of formula I with a reducing agent containing siloxane bonds in an organic solvent to form a mixed liquid; S2: The mixed liquid is continuously fed into a microreactor filled with a finite-domain MOF-supported catalyst for reduction reaction; S3: Continuously collect the effluent from the microreactor to obtain compound II; The confined MOFs supported catalyst comprises a metal-organic framework support with rigid channels, wherein metal trifluoromethanesulfonate is coordinated and anchored within the rigid channels.

[0008] Furthermore, the metal-organic framework carrier is selected from either UiO-66 or MIL-101, and the pore size of the rigid channel is 1.2 nm to 2.5 nm.

[0009] Furthermore, the metal trifluoromethanesulfonate is selected from scandium trifluoromethanesulfonate and bismuth trifluoromethanesulfonate, and the loading amount of the metal trifluoromethanesulfonate on the metal-organic framework support is 0.1 mmol / g to 0.8 mmol / g.

[0010] Furthermore, the reducing agent containing siloxane bonds is polymethylhydrosiloxane, wherein the active hydrogen content of the polymethylhydrosiloxane is 1.50%~1.65% by mass, and the kinematic viscosity at 25°C is 15cSt~40cSt.

[0011] Furthermore, the organic solvent is selected from toluene, xylene, and chlorobenzene.

[0012] Furthermore, the temperature of the reaction zone within the microreactor is set to... The residence time of the mixed liquid in the microreactor is 2 to 10 minutes; the confined MOFs supported catalyst is pre-treated for dehydration before loading, and its water content is less than 0.5%.

[0013] A continuous-flow synthesis system for implementing the above synthesis method includes: The feeding module is used to mix and convey the mixed liquid; A fixed-bed microreactor, wherein the input end of the fixed-bed microreactor is connected to the feed module, and the interior is filled with the confined MOFs supported catalyst; An online spectral detection module is installed at the output end of the fixed-bed microreactor to monitor the component conversion rate of the effluent in real time. The central control unit is communicatively connected to both the feeding module and the online spectral detection module, and is used to control the conveying flow rate of the feeding module in a closed loop based on the feedback signal from the online spectral detection module.

[0014] Furthermore, the online spectral detection module includes an online infrared spectral probe; The central control unit is configured to: extract in real time the 1000cm data monitored by the online infrared spectral probe. -1 Up to 1100cm -1 The characteristic peak ratio data of silyl ether bonds and carbon-carbon bonds within the frequency band is used to automatically reduce the conveying flow rate of the feeding module to extend the residence time when the calculated conversion rate is lower than a preset threshold.

[0015] Furthermore, the feeding module includes a raw material storage tank, a premixer connected to the raw material storage tank, and a horizontal flow pump disposed between the premixer and the fixed bed microreactor, and the central control unit is electrically connected to the horizontal flow pump.

[0016] Furthermore, it also includes a post-processing crystallization module, the input end of which is connected to the pipeline output end of the online spectral detection module, for washing and recrystallizing the effluent.

[0017] In summary, compared with the prior art, the present invention has the following advantages: 1. In this invention, the specific pore size of the metal-organic framework carrier is precisely matched with the three-dimensional dimensions of the substrate molecule. Rigid channels completely lock the spatial conformation of the substrate molecule, thus physically blocking the reductant from flowing out. The path of attack is determined, thereby guiding substrate generation with extremely high selectivity. Configuration; 2. In this invention, the highly enriched Sc and Bi ions within the MOF pores not only efficiently activate the hemiacetal hydroxyl groups of the substrate but also exert a strong polarization pull on the Si-H bonds in the polymethylhydrosiloxane entering the pores. The synergistic dual polarization of the pore microenvironment and the metal Lewis acid, combined with the extremely high mass transfer surface area of ​​the microchannels, enables the inert polymethylhydrosiloxane to rapidly undergo deep reduction under mild conditions, breaking the conventional bias that replacing triethylsilane with polymethylhydrosiloxane requires increased temperature or the use of highly toxic catalysts. 3. In this invention, the kinematic viscosity of polymethylhydrosiloxane is defined, and a probe is introduced, not for simple flow display, but to accurately capture the transient ratio of silicon-ether bond demise and carbon-carbon bond formation in a specific frequency band. The flow rate is adjusted in a closed loop by the central control unit. The two work together to fundamentally ensure the long-term stable operation of the gas-liquid-solid multiphase reaction in the microchannel. Attached Figure Description

[0018] Figure 1 This is the synthetic route of the present invention; Figure 2 This is a schematic diagram of the continuous flow synthesis system of the present invention. Detailed Implementation

[0019] The technical solution of the present invention will be further described in detail below through specific embodiments, but the present invention is not limited to these embodiments. Example 1

[0020] Ten g of synthesized UiO-66 crystals with pore sizes of approximately 1.2 nm–1.5 nm were placed in a vacuum tube furnace and activated at 150 °C for 12 hours to remove free solvent from the pores. Under anhydrous inert gas protection, the crystals were suspended in anhydrous toluene solution containing 2.0 g of scandium trifluoromethanesulfonate and refluxed with stirring for 24 hours to ensure sufficient coordination and anchoring of the metal centers into the pores. After centrifugation and washing, the crystals were dried under high vacuum at 100 °C for 12 hours to obtain a powdered supported catalyst with a water content of less than 0.5% and a measured Sc loading of 0.35 mmol / g. Example 2

[0021] Change conditions: This embodiment uses the aforementioned continuous flow synthesis system. The system includes: a raw material storage tank as a feed module, a premixer and a horizontal pump, a stainless steel fixed-bed microreactor with an effective volume of 50 mL, the reactor being filled with the catalyst prepared in Example 1 and quartz sand to control the pressure drop, an in-line FTIR probe at the output end, a PLC central control unit and a post-processing crystallization module.

[0022] The specific process steps are as follows: The system was pre-cooled to 10°C. 200g of protected compound I substrate and 45g of polymethylhydrosiloxane (PMHS, kinematic viscosity 20cSt, active hydrogen content 1.58%) were dissolved in 1000mL of anhydrous toluene and added to the raw material storage tank.

[0023] Turn on the horizontal flow pump and continuously pump the mixed liquid into the fixed bed microreactor at an initial flow rate of 10 mL / min. The residence time of the liquid in the reaction zone is about 5 minutes.

[0024] In-line FTIR probe real-time scanning 1000cm -1 Up to 1100cm -1 Frequency band. The PLC central control unit receives spectral data in real time. When the system determines that the substrate conversion rate calculated by the ratio of characteristic peaks of silyl ether bonds and carbon-carbon bonds is less than 99%, it automatically issues a command to reduce the flow rate of the advection pump to 8 mL / min to prolong the residence time until the conversion rate recovers to the preset threshold.

[0025] After the effluent passes the test, it is directly introduced into the post-treatment crystallization kettle, where water is added to wash and separate the silicone resin byproducts. After concentrating the organic phase, methanol is added for recrystallization.

[0026] After 100 minutes of continuous and stable operation, 185.5 g of a white solid, namely compound II, was collected. HPLC analysis showed a separation yield of 95.2%, with a diastereomeric excess percentage (de value) of 99.9%, indicating almost no diastereomeric residues. Impurities were detected. Example 3

[0027] By adding a very small amount of acid, such as hydrochloric acid in methanol or p-toluenesulfonic acid, and stirring at room temperature for a short while, the four TMS protecting groups will detach and become a byproduct (methoxytrimethylsilane, which is highly volatile). After concentrating the reaction solution, free dalgrazine is directly obtained. Example 4

[0028] Change condition: The pore size of MOFs in this embodiment exceeds the specified range. The difference between this comparative example and Example 2 is that the catalyst packed in the microreactor was replaced with Sc(OTf)3 immobilized in mesoporous MOFs with a pore size of approximately 3.2 nm. The effluent was collected and analyzed; the conversion rate was 94.5%, but the diastereomeric excess percentage (de value) decreased significantly to 88.4%.

[0029] Results Analysis: Because the pore size exceeded the critical range of 1.2 nm to 2.5 nm, the substrate molecules had excessive physical space within the pores, making it impossible to lock their conformation. The PMHS reducing agent obtained [something] from the substrate. Opportunities for frontal attacks led to a large number of The formation of isomeric impurities demonstrates the non-obviousness of limiting the pore size to 1.2 nm to 2.5 nm in this application for achieving extreme stereoselectivity. Example 5

[0030] Change condition: The kinematic viscosity of the reducing agent in this embodiment exceeds the specified range. The difference between this comparative example and Example 2 is that the kinematic viscosity of the polymethylhydrosiloxane used is 100 cSt at 25°C, which exceeds the limited range of 15 cSt to 40 cSt. After 25 minutes of operation, the pressure drop in the continuous flow system increased sharply, and the conversion rate of the collected effluent was only 71.2%.

[0031] Results analysis: High-viscosity PMHS cannot form a good gas-liquid-solid multiphase mass transfer interface in the microchannel reactor, and the silicone resin byproducts generated in the reaction easily adhere to the catalyst bed, causing channel blockage. Therefore, a residence time of 5 minutes is far from sufficient to complete the reaction. This demonstrates the absolute necessity of limiting PMHS to low viscosity for ensuring long-term, efficient operation of continuous flow systems. Example 6

[0032] Change condition: The reaction temperature in this embodiment exceeds the specified range. The difference between this comparative example and Example 2 is that the temperature of the reaction zone in the microreactor was set and maintained at 50°C, exceeding the defined range of 0°C to 25°C. The reaction proceeded extremely rapidly, but a large amount of deprotected byproducts were detected in the effluent, which were determined to be due to the breakage of trimethylsilyl ether bonds, causing the overall yield to plummet to 75.3% and the de value to be 93.1%.

[0033] Results Analysis: Although heating can accelerate the reaction, excessively high temperatures, under the strong activation of the Sc / Bi Lewis acid, lead to instability of the protecting groups on the substrate, triggering serious side reactions. This demonstrates that the mild conditions for achieving efficient conversion at room temperature in this invention are the optimal solution balancing yield and purity.

[0034] Comparative Example 1 Using existing technology, BF3·Et2O+Et3SiH was reacted in a batch at -78℃ for 6 hours, with a comprehensive yield of 86.1% and a de value of 96.5%, but a large amount of acidic fluoride-containing wastewater was generated.

[0035] The conventional solid resin Amberlyst-15+PMHS was used in a batch reactor at -10℃ for 4 hours, with a comprehensive yield of 90.6% and a de value of 98.2%. The resin is prone to deactivation.

[0036] In comparison, Embodiment 2 of the present invention has achieved significant technical progress in terms of reaction efficiency, stereoselectivity, environmental friendliness, and ease of operation.

[0037] The embodiments of the present invention are not limited to those described above. Without departing from the spirit and scope of the present invention, those skilled in the art can make various changes and improvements to the present invention in form and detail, and these are all considered to fall within the protection scope of the present invention.

Claims

1. A 2-chloro A green synthesis process for pyranose-1-yl)-4'-ethoxydiphenylmethane, using compound I as a reaction substrate to prepare compound II, is characterized by: Includes the following steps: S1: Dissolve the compound of formula I with a reducing agent containing siloxane bonds in an organic solvent to form a mixed liquid; S2: The mixed liquid is continuously fed into a microreactor filled with a finite-domain MOF-supported catalyst for reduction reaction; S3: Continuously collect the effluent from the microreactor to obtain compound II; The confined MOFs supported catalyst comprises a metal-organic framework support with rigid channels, wherein metal trifluoromethanesulfonate is coordinated and anchored within the rigid channels.

2. A 2-chloro-1 ... The green synthesis process of pyranose-1-yl)-4'-ethoxydiphenylmethane is characterized by: The metal-organic framework carrier is selected from either UiO-66 or MIL-101, and the pore size of the rigid channel is 1.2 nm to 2.5 nm.

3. A 2-chloro-1-propagation method according to claim 1 The green synthesis process of pyranose-1-yl)-4'-ethoxydiphenylmethane is characterized by: The metal trifluoromethanesulfonate is selected from scandium trifluoromethanesulfonate and bismuth trifluoromethanesulfonate, and the loading amount of the metal trifluoromethanesulfonate on the metal-organic framework support is 0.1 mmol / g to 0.8 mmol / g.

4. A 2-chloro-1 ... The green synthesis process of pyranose-1-yl)-4'-ethoxydiphenylmethane is characterized by: The reducing agent containing siloxane bonds is polymethylhydrosiloxane, the active hydrogen content of which is 1.50% to 1.65% by mass, and the kinematic viscosity at 25°C is 15 cSt to 40 cSt.

5. A 2-chloro-1 ... The green synthesis process of pyranose-1-yl)-4'-ethoxydiphenylmethane is characterized by: The organic solvent is selected from toluene, xylene, and chlorobenzene.

6. A 2-chloro-1 ... The green synthesis process of pyranose-1-yl)-4'-ethoxydiphenylmethane is characterized by: The temperature of the reaction zone inside the microreactor is set to... The residence time of the mixed liquid in the microreactor is 2 to 10 minutes; the confined MOFs supported catalyst is pre-treated for dehydration before loading, and its water content is less than 0.5%.

7. A continuous-flow synthesis system for implementing the synthesis method according to any one of claims 1 to 6, characterized in that, include: The feeding module is used to mix and convey the mixed liquid; A fixed-bed microreactor, wherein the input end of the fixed-bed microreactor is connected to the feed module, and the interior is filled with the confined MOFs supported catalyst; An online spectral detection module is installed at the output end of the fixed-bed microreactor to monitor the component conversion rate of the effluent in real time. The central control unit is communicatively connected to both the feeding module and the online spectral detection module, and is used to control the conveying flow rate of the feeding module in a closed loop based on the feedback signal from the online spectral detection module.

8. The continuous flow synthesis system according to claim 7, characterized in that: The online spectral detection module includes an online infrared spectral probe; The central control unit is configured to: extract in real time the characteristic peak ratio data of silicon-ether bonds and carbon-carbon bonds in the 1000cm-1 to 1100cm-1 frequency band monitored by the online infrared spectroscopy probe; and automatically reduce the conveying flow rate of the feeding module to extend the residence time when the calculated conversion rate is lower than a preset threshold.

9. The continuous flow synthesis system according to claim 7, characterized in that: The feeding module includes a raw material storage tank, a premixer connected to the raw material storage tank, and a horizontal flow pump disposed between the premixer and the fixed bed microreactor. The central control unit is electrically connected to the horizontal flow pump.

10. The continuous flow synthesis system according to claim 7, characterized in that: It also includes a post-processing crystallization module, the input of which is connected to the pipeline output of the online spectral detection module, for washing and recrystallizing the effluent.

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