Process for catalytic synthesis of acetylenglitazin and active support catalyst

Abstract

This invention discloses a process and active carrier catalyst for the catalytic synthesis of acetyl empagliflozin. The process utilizes a yeast cell wall-mediated active carrier nickel-phosphorus composite catalyst. The catalyst is activated in a water / glycerol mixed solvent via microwave-ultrasound dual-field synergistic activation, catalyzing the reaction of compound 5 with compound 4 to obtain compound 3. In a supercritical CO2 / ionic liquid system, leveraging the photoisomerization properties of spiropyran-quaternary ammonium iodide, under low-voltage electrocatalysis and UV-Vis switching conditions, the directional glycosylation reaction of compound 3 with compound 2 is achieved to obtain compound 1. This invention utilizes the porous structure and functional groups of the yeast cell wall to stabilize nano-nickel-phosphorus particles, improving catalytic efficiency and reusability. Through the synergistic guiding effect of photoresponsive molecules and ionic liquids, high selectivity of the reaction is achieved. The entire process uses green solvents, and a closed-loop catalyst recovery process is established, offering advantages such as environmental friendliness, low cost, and high product purity.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemical synthesis, specifically to the design of a process and active support catalyst for the catalytic synthesis of acetyl empagliflozin. Background Technology

[0002] Empagliflozin is a highly selective SGLT2 inhibitor. Its synthetic route typically involves key steps related to the construction of the aromatic ring and the introduction of the glucoside.

[0003] In existing catalytic synthesis technologies, the catalysts used are usually expensive and have short lifespans. Traditional aryl coupling reactions often use expensive palladium-based catalysts. Although nickel catalysts, as alternatives, are cheaper, they have low catalytic activity, and nanoparticles are prone to agglomeration leading to deactivation. They also have short cycle lifespans and can usually only be reused about 3 times.

[0004] Meanwhile, commonly used catalysts exhibit poor stereoselectivity in glycosylation reactions, and controlling the stereoconfiguration of the glycosidic bond (i.e., α / β isomers) when introducing glucose units is a challenge. Traditional methods typically rely on low temperatures of -78°C, strong Lewis acids, and strictly anhydrous conditions, which are not only energy-intensive but also result in numerous side reactions and make it difficult to precisely control the directional coupling at the C1 position. Furthermore, catalyst recovery rates are low, and discarded metal catalyst supports are often difficult to dispose of simply, easily leading to heavy metal pollution and resource waste, and lacking a closed-loop recovery mechanism. Summary of the Invention

[0005] This invention aims to solve the above problems by providing a novel process for synthesizing empagliflozin intermediates using a nickel-phosphorus composite catalyst mediated by the cell wall of brewer's yeast and combining photo-electro-catalyzed synthesis.

[0006] The objective of this invention is achieved through the following technical solution: The synthesis process of empagliflozin intermediate, comprising a nickel-phosphorus composite catalyst mediated by the cell wall of brewer's yeast and including the following steps: S1: Compound of Formula 5, compound of Formula 4, dipinacol diboron, potassium acetate, and nickel-phosphorus composite catalyst on living support were placed in a water / glycerol mixed solvent and reacted at 65°C for 4 h under microwave-ultrasound dual-field synergistic activation to obtain compound of Formula 3. S2: Compound of Formula 3, compound of Formula 2 β-D-glucose pentaacetate, and spiropyran-quaternary ammonium iodide (SP-I⁻) were placed in a supercritical CO2 / ionic liquid mixture for glycosyl-directed low-voltage electrocatalysis, and continuous irradiation with 365nm ultraviolet light was used to activate the conversion of SP-I⁻ to MC-I⁻. The reaction was carried out at 75℃ for 6h. S3: Turn off the ultraviolet light and turn on the 550nm visible light to restore MC-I⁻ to SP-I⁻ and dissociate it from the product. At the same time, reduce the system pressure to atmospheric pressure, and the supercritical CO2 will turn into gas and escape. The product will precipitate in the ionic liquid. Filter and collect the Formula 1 compound. The ionic liquid and SP-I⁻ can be recycled.

[0007] Furthermore, this approach utilizes brewer's yeast by leveraging its naturally porous cell wall structure (pore size 10-50 nm) and abundant surface functional groups (carboxyl-COOH, amino-NH2, hydroxyl-OH), rather than relying on the yeast's respiration, metabolism, or other biological functions. The entire process can be divided into two steps: catalyst preparation and coupling reaction. The yeast's survival status is only significant in the first step of catalyst preparation; its survival is no longer required in the second step of the coupling reaction. In the first step, the cell wall of the live yeast is in a flexible state, and the surface functional groups (-COOH, -NH2) actively bind to Ni. 2 ⁺, guides Ni-P nanoparticles to grow in situ inside the cell wall, avoiding particle aggregation; In the second step, after the yeast dies at 65°C, the polysaccharides and proteins in the cell wall of the dead yeast coagulate to form a rigid porous framework. The previously in-situ grown Ni-P nanoparticles are firmly fixed by the functional groups of the cell wall. The porous structure of the framework can adsorb substrates (i.e., compounds of formula 5 and formula 4). The substrates can quickly diffuse through the pores to the internal Ni-P active sites, increasing the local reaction concentration. This is more conducive to mass transfer than the dynamic pore size of live yeast.

[0008] Furthermore, the in vivo carrier nickel-phosphorus composite catalyst is a cell wall-mediated in vivo carrier nickel-phosphorus composite catalyst. Its preparation process includes taking brewer's yeast, activating the carboxyl and amino groups on the cell wall surface with 0.1 mol / L hydrochloric acid, adding nickel chloride hexahydrate and sodium hypophosphite as a reducing agent, and growing nickel-phosphorus nanoparticles in situ on the yeast cell wall through biomineralization at 30°C. During the reaction, the polysaccharide / protein structure of the yeast cell wall coordinates, i.e., -COOH→Ni 2 ⁺、-NH2→Ni 2 ⁺, stabilizes Ni-P NPs, and finally forms a living support nickel-phosphorus composite catalyst, denoted as Yeast@Ni-P.

[0009] Preferably, the nickel-phosphorus nanoparticles have a particle size of 2-5 nm.

[0010] Furthermore, the in-situ preparation of catalysts can be achieved by utilizing the natural functional groups of living microorganisms, without the need for complex equipment. Moreover, the porous structure (pore size 10-50 nm) of the living carrier can actively adsorb substrates (i.e., compounds of formula 5 and formula 4), thereby increasing the local concentration.

[0011] Furthermore, after the S1 step reaction is completed, Yeast@Ni-P is collected by centrifugation at 3000 rpm for 10 min, washed three times with deionized water, and then added to the next round of reaction.

[0012] Furthermore, when the activity of Yeast@Ni-P drops to 50%, yeast autolysin is added, and the cell wall is enzymatically hydrolyzed at 50°C to release Ni-P NPs. Ni is then recovered by adsorption with activated carbon. The hydrolysate can be used as a trace co-catalyst for the next round of reaction, increasing the yield by 2%-3%.

[0013] As a preferred option, Yeast@Ni-P can be reused 8 times, with the yield still reaching 65% on the 8th use, which is far superior to the 3-use lifetime of traditional nickel catalysts.

[0014] Furthermore, a centrifugal-yeast autolysis closed-loop process is formed, realizing the full recycling of catalyst-carrier-waste, with no solid waste discharge, and utilizing the yeast's own components to improve reaction efficiency, breaking through the traditional thinking of recycling as degradation.

[0015] Furthermore, under 365nm ultraviolet light irradiation, the CO bond inside the spiropyran-quaternary ammonium iodide breaks, generating a cyanine structure with strong electron-donating ability, namely MC-I⁻. MC-I⁻ forms π-π stacking with the aromatic ring in the compound of formula 3. Under 550nm visible light irradiation, it is restored to the spiropyran structure, namely SP-I⁻, releasing the product.

[0016] Furthermore, SP-I⁻ transforms into MC-I⁻ under ultraviolet light. Its cationic structure forms a cation-cation repulsion with [BMIM]⁺. Under the condition of opposite attraction, MC-I⁻ is forced to approach the ester oxygen of the sugar group. Through π-π stacking, that is, the conjugated structure of MC and the glucose ring, the orientation of the sugar group is further fixed, so that the C1 position of the sugar group is precisely aligned with the aromatic ring of the compound of formula 3.

[0017] Furthermore, the S2 step electrocatalysis is a three-electrode catalytic system, including a working electrode of graphite felt, a reference electrode of Ag / Ag⁺, and a counter electrode of platinum wire, with an applied voltage of 0.8V; the ionic liquid is 1-butyl-3-methylimidazolium tetrafluoroborate.

[0018] Furthermore, the glucose unit of compound 2 achieves directional adsorption through the interaction of polar groups with ionic liquids, which pulls the glycosyl end of compound 8 toward the working electrode surface, so that the C1 site of the glycosyl group (i.e. the site coupled with compound 3) preferentially contacts the MC-I⁻ activated compound 3, thereby reducing the incidence of side reactions.

[0019] Furthermore, the ester oxygen group on the compound of formula 2 combines with the [BMIM]⁺ of the ionic liquid through Coulomb forces to form an ion pair. The lone pair electrons of the ester oxygen group undergo weak coordination with the π electron cloud of the imidazole ring of [BMIM]⁺, similar to the crown ether-metal ion interaction, which stabilizes the orientation of the sugar group and pulls the reaction site of the sugar group toward the electrode surface.

[0020] Furthermore, in-situ targeting is achieved by utilizing the functional groups of the substrate itself, eliminating the need for additional targeting agents, and low-voltage electrocatalysis avoids glycosylation.

[0021] Furthermore, the microwave-ultrasound dual-field synergistic activation consists of 300W microwaves and 40kHz ultrasound.

[0022] Furthermore, the microwave-ultrasound dual-field synergistic activation addresses the issue of slightly low Ni catalytic activity while reducing energy consumption. Microwaves accelerate the collision between the substrate and the catalyst's active centers, while ultrasound temporarily opens the porous structure of the yeast cell wall through cavitation, releasing more Ni-P active sites. The synergistic effect of both technologies brings Ni's catalytic activity close to that of Pd, while avoiding substrate decomposition caused by high temperatures.

[0023] Furthermore, in the supercritical CO2 / ionic liquid mixed system, the volume ratio of supercritical CO2 to [BMIM]BF4 is 3:1.

[0024] Furthermore, supercritical CO2 dissolves the substrate, and ionic liquids conduct current.

[0025] Furthermore, after filtering and collecting the Formula 1 compound, the ionic liquid is recycled with SP-I⁻.

[0026] As a preferred option, SP-I⁻ can be repeated 10 times with a loss rate of <3%.

[0027] In summary, compared with the prior art, the present invention has the following advantages: 1. In this invention, the functional group coordination and porous structure of the yeast cell wall are utilized to control the Ni-P particle size to 2-5 nm, avoiding the aggregation problem of traditional nickel catalysts. Microwave heating accelerates the reaction, and ultrasonic cavitation temporarily opens the cell wall pores, exposing more active sites. The synergy of these two factors allows the activity of the inexpensive Ni catalyst to approach that of the expensive Pd catalyst. Simultaneously, the dead yeast cell wall forms a rigid framework, and its porous structure actively adsorbs and enriches the substrate, greatly increasing the local substrate concentration in the reaction. 2. In this invention, the photoisomerization properties of SP-I⁻ / MC-I⁻ are utilized. Under ultraviolet light, MC-I⁻ stacks with the aromatic ring of the substrate. Combined with the Coulombic guiding effect of the ionic liquid on the oxygen of the glycosyl ester group, it acts like "molecular tweezers" to precisely align the C1 position of the glycosyl group with the reaction site, significantly reducing side reactions. Moreover, the crude product has high purity, eliminating the cumbersome ethyl acetate purification or column chromatography steps in traditional processes, and exhibiting extremely high stereoselectivity and product purity. 3. In this invention, water / glycerol, supercritical CO2 and ionic liquids are used to replace traditional organic solvents. They are non-toxic and easy to separate, have a low reaction temperature, and utilize low-voltage electrocatalysis, which significantly reduces energy consumption. They have the advantages of being both green and environmentally friendly and having low energy consumption. 4. In this invention, Yeast@Ni-P can be reused 8 times, and the yield can still reach 65% on the 8th time. After the catalyst is deactivated, the cell wall is enzymatically hydrolyzed by yeast autolysin, and the released Ni is recovered through activated carbon. The hydrolysate is directly used as a co-catalyst for the next round of reaction, which completely breaks through the thinking that catalyst recovery is degradation or waste, and forms a closed-loop recycling process with no solid waste discharge. Attached Figure Description

[0028] Figure 1 This is a synthetic route diagram for the present invention. Detailed Implementation

[0029] To explain in detail the technical content, structural features, objectives, and effects of the present invention, further explanation is provided below with reference to specific embodiments.

[0030] Example 1 Living support nickel-phosphorus composite catalyst: The carboxyl and amino groups on the cell wall surface of brewer's yeast were activated with 0.1 mol / L hydrochloric acid. Nickel chloride hexahydrate (5 g / L) and sodium hypophosphite (a reducing agent) were added, and biomineralization was carried out at 30°C to induce the in-situ growth of Ni-P NPs in the yeast cell wall. The particle size was 2-5 nm. The polysaccharide / protein structure of the yeast cell wall underwent coordination, with -COOH → Ni. 2 ⁺、-NH2→Ni 2 ⁺, stabilizes Ni-P NPs, forming a living carrier-metal active center composite system, denoted as Yeast@Ni-P.

[0031] Example 2 Compound of Formula 5 (36.6 g, 0.1 mol), compound of Formula 4 (30.5 g, 0.12 mol), potassium acetate (29.5 g, 0.3 mol), Yeast@Ni-P (1.5 g), and a water / glycerol mixed solvent (volume ratio 4:1, total 300 mL) were added to the reaction flask. The reaction was carried out by the synergistic effect of 300 W microwave and 40 kHz ultrasound to generate local high temperature and high pressure cavitation bubbles, which broke the passivation layer on the surface of Ni-P NPs. The reaction was carried out at 65 °C for 4 h.

[0032] After the reaction was complete, the mixture was cooled to room temperature, filtered, washed with water, concentrated, and recrystallized with ethanol to give 32.55 g of white solid, namely compound 3. The product yield was 78.6% and the product purity was 99%.

[0033] Example 3 The residual system was collected by centrifugation at 3000 rpm for 10 min to obtain Yeast@Ni-P, washed three times with deionized water, and reused in the next round of reaction. It can be reused up to eight times, with the yield still reaching 65% in the eighth round, which is much higher than the three-times lifetime of traditional nickel catalysts. When the catalyst activity dropped to 50%, yeast autolysin (addition amount of 0.5 g / L) was added, and the cell wall was enzymatically hydrolyzed at 50 °C to release Ni-P NPs. Ni was recovered by adsorption with activated carbon (recovery rate >95%). The enzymatic hydrolysate contains glucose and amino acids, which can be used as a trace co-catalyst for the next round of reaction (increasing the yield by 2%~3%).

[0034] Example 4 Compound of Formula 3 (20.7 g, 0.05 mol), compound of Formula 2 (39 g, 0.1 mol), SP-I⁻ (2.0 g, metal-free, cost < 80 yuan / g), and supercritical CO2 / ionic liquid mixed system (volume ratio 3:1, 500 mL) were added to the reaction flask. A three-electrode system (working electrode: graphite felt, reference electrode: Ag / Ag⁺, counter electrode: platinum wire) was applied with a voltage of 0.8V and continuously irradiated with 365nm ultraviolet light to activate the conversion of SP-I⁻ to MC-I⁻, which forms π-π stacking with the aromatic ring of compound 3. The reaction was carried out at 75℃ for 6 hours. After the reaction was completed, the ultraviolet light was turned off and the visible light at 550nm was turned on. MC-I⁻ reverted to SP-I⁻ and dissociated from the product. The system pressure was reduced from 8MPa to atmospheric pressure, and supercritical CO2 was converted into gas and escaped. The product precipitated in the ionic liquid. Compound 1 is collected by filtration. The crude product has a purity of ≥98.5%. It does not require purification with ethyl acetate. The ionic liquid and SP-I⁻ can be recycled up to 10 times with a loss rate of <3%.

[0035] 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 process for the catalytic synthesis of acetyl empagliflozin and an active support catalyst, characterized in that, The synthesis process of empagliflozin intermediates, including a nickel-phosphorus composite catalyst mediated by the cell wall of brewer's yeast, comprises the following steps: S1: Compound of Formula 5, compound of Formula 4, dipinacol diboron, potassium acetate, and nickel-phosphorus composite catalyst on living support were placed in a water / glycerol mixed solvent and reacted at 65°C for 4 h under microwave-ultrasound dual-field synergistic activation to obtain compound of Formula 3. S2: Compound of Formula 3, compound of Formula 2 β-D-glucose pentaacetate, and spiropyran-quaternary ammonium iodide (SP-I⁻) were placed in a supercritical CO2 / ionic liquid mixture for glycosyl-directed low-voltage electrocatalysis, and continuous irradiation with 365nm ultraviolet light was used to activate the conversion of SP-I⁻ to MC-I⁻. The reaction was carried out at 75℃ for 6h. S3: Turn off the ultraviolet light and turn on the 550nm visible light to restore MC-I⁻ to SP-I⁻ and dissociate it from the product. At the same time, reduce the system pressure to atmospheric pressure, and the supercritical CO2 will turn into gas and escape. The product will precipitate in the ionic liquid. Filter and collect the Formula 1 compound. The ionic liquid and SP-I⁻ can be recycled.

2. The process for catalytic synthesis of empagliflozin intermediates according to claim 1, and the active support catalysis, characterized in that: The in vivo carrier nickel-phosphorus composite catalyst is a brewer's yeast cell wall-mediated in vivo carrier nickel-phosphorus composite catalyst. Its preparation process includes taking brewer's yeast, activating the carboxyl and amino groups on the cell wall surface with 0.1 mol / L hydrochloric acid, adding nickel chloride hexahydrate and reducing agent sodium hypophosphite, and growing nickel-phosphorus nanoparticles in situ on the yeast cell wall through biomineralization at 30°C. During the reaction, the polysaccharide / protein structure of the yeast cell wall coordinates through a process called -COOH→Ni. 2 ⁺、-NH2→Ni 2 ⁺, stabilizes Ni-P NPs, and finally forms a living support nickel-phosphorus composite catalyst, denoted as Yeast@Ni-P.

3. The process for catalytic synthesis of empagliflozin intermediates according to claim 1, and the active support catalysis, characterized in that: After the S1 step reaction is completed, collect Yeast@Ni-P by centrifugation at 3000 rpm for 10 min, wash it 3 times with deionized water, and then put it back into the next round of reaction.

4. The process for catalytic synthesis of empagliflozin intermediates according to claim 3, and the active support catalysis, characterized in that: When the activity of Yeast@Ni-P drops to 50%, yeast autolysin is added, and the cell wall is enzymatically hydrolyzed at 50°C to release Ni-P NPs. Ni is then recovered by adsorption with activated carbon. The hydrolysate can be used as a trace co-catalyst for the next round of reaction, increasing the yield by 2%-3%.

5. The process for catalytic synthesis of empagliflozin intermediates according to claim 1, and the active support catalysis, characterized in that: Under 365 nm ultraviolet light irradiation, the CO bond inside the spiropyran-quaternary ammonium iodide breaks, generating a cyanine structure with strong electron-donating ability, namely MC-I⁻. MC-I⁻ forms a π-π stack with the aromatic ring in the compound of formula 3. Under 550 nm visible light irradiation, it is restored to the spiropyran structure, namely SP-I⁻, and the product is released.

6. The process for catalytic synthesis of empagliflozin intermediates according to claim 1, and the active support catalysis, characterized in that: The S2 step electrocatalysis is a three-electrode catalytic system, including a working electrode of graphite felt, a reference electrode of Ag / Ag⁺, and a counter electrode of platinum wire, with an applied voltage of 0.8V; the ionic liquid is 1-butyl-3-methylimidazolium tetrafluoroborate.

7. The process for catalytic synthesis of empagliflozin intermediates according to claim 1, and the active support catalysis, characterized in that: The microwave-ultrasound dual-field synergistic activation consists of 300W microwave and 40kHz ultrasound.

8. The process for catalytic synthesis of empagliflozin intermediates according to claim 1, and the active support catalysis, characterized in that: In the supercritical CO2 / ionic liquid mixed system, the volume ratio of supercritical CO2 to [BMIM]BF4 is 3:

1.

9. The process for catalytic synthesis of empagliflozin intermediates according to claim 1, and the active support catalysis, characterized in that: After filtration and collection of Formula 1 compounds, the ionic liquid and SP-I⁻ are recycled.

Images