Method for continuously synthesizing dapagliflozin intermediate

Abstract

The invention relates to a method for continuously synthesizing a dapagliflozin intermediate, and belongs to the technical field of drug intermediate synthesis. The method comprises the following steps: mixing 5-bromo-2-chloro-4 '-ethoxydiphenylmethane, a photocatalyst and THF (tetrahydrofuran), introducing the mixture into an ultraviolet light catalytic micro-channel for pre-activation to generate an aryl free radical intermediate, namely a pre-activation solution, carrying out contact reaction on the pre-activation solution and a THF solution of 2, 3, 4, 6-tetra-O-trimethylsilyl-D-glucolactone in a low-temperature coupling area of a micro-reactor, and carrying out purification, purification and purification to obtain the aryl free radical intermediate. The reaction liquid is introduced into a dynamic quenching zone and is mixed with supercritical CO2 on line, an intermediate I is obtained through supercritical fluid extraction and separation, and the photocatalyst is recycled; the method has the advantages of high reaction efficiency, convenience in catalyst recovery and simplicity in product separation.

Description

Technical Field

[0001] The present invention relates to a method for continuously synthesizing a dapagliflozin intermediate, belonging to the field of preparation of pharmaceutical intermediates. Background Art

[0002] Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor, which is a potential treatment for type 1 and type 2 diabetes. It is jointly developed by Bristol-Myers Squibb and AstraZeneca. It is applicable to patients with type 2 diabetes and is used as an adjunct to diet and exercise to improve blood glucose control. It works by inhibiting sodium-glucose cotransporter 2 to prevent glucose from being reabsorbed into the blood, so that the excess glucose is excreted through urine. Whether used alone or in combination with other drugs, it can significantly reduce HbA1c and fasting blood glucose in patients with type 2 diabetes.

[0003] In the process of synthesizing the key intermediate of dapagliflozin, homogeneous palladium catalysts are mostly used in the existing processes. Although their catalytic activity is relatively high, the separation of the catalyst from the product after the reaction requires complex steps such as extraction and distillation, resulting in the loss of palladium metal. This not only increases the production cost, but also poses a risk of heavy metal pollution, is not friendly to the environment. Moreover, the activation of aryl halides in the reaction process depends on high temperature or strong base conditions, leading to many side reactions (such as dehalogenation, self-coupling, etc.). Therefore, the selectivity of the target product is usually less than 80%. In addition, the reaction mass transfer and heat transfer efficiency of traditional batch reactors is low, and the coupling step takes several hours to complete, seriously restricting the production efficiency. At the same time, the separation of the product usually relies on multiple solvent extractions and column chromatography purification, which consumes a large amount of organic solvents during the process, and the energy consumption of high-temperature vacuum distillation is relatively large, resulting in poor environmental protection and economy of the overall process.

[0004] Therefore, developing a synthesis process of dapagliflozin intermediate that integrates efficient catalysis, continuous operation, catalyst recycling and green separation has become the key direction to break through the existing technical barriers. While improving the reaction rate and selectivity, it realizes the recycling of resources and the reduction of energy consumption to meet the urgent needs of the pharmaceutical industry for green manufacturing. Summary of the Invention

[0005] Aiming at the problems of low reaction efficiency, difficult catalyst recovery and high energy consumption in the separation of products existing in the existing synthesis process of dapagliflozin intermediate, the present invention provides a continuous synthesis method based on the combination of microreactors and supercritical fluid technology. Through the integrated design of photocatalytic pre-activation, low-temperature coupling and dynamic quenching extraction, the high-efficiency and high-selectivity synthesis of the target intermediate is realized, and the catalyst recycling is completed synchronously, significantly improving the production economy and environmental protection.

[0006] The object of the present invention is achieved by the following technical solutions. A method for continuously synthesizing a dapagliflozin intermediate, the method comprising the following steps:

[0007] S1: Mix 5-bromo-2-chloro-4'-ethoxydiphenylmethane, a photocatalyst and THF, introduce ultraviolet light for catalytic microchannel pre-activation to generate an aryl radical intermediate, namely a pre-activated solution;

[0008] S2: Contact and react the pre-activated solution of step S1 with a THF solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone in the low-temperature coupling zone of a microreactor to obtain a reaction solution;

[0009] S3: Introduce the reaction solution of step S2 into a dynamic quenching zone, mix it online with supercritical CO2, and separate the intermediate I by supercritical fluid extraction and recover the photocatalyst.

[0010] Preferably, the photocatalyst is a palladium nanoparticle composite supported on carbon nitride, wherein the loading amount of palladium is 0.1-1.0 wt%, and the dosage of the photocatalyst is 0.1-1% of the molar amount of 5-bromo-2-chloro-4'-ethoxydiphenylmethane.

[0011] Preferably, the microreactor is divided into three independent temperature control zones, including a photocatalytic zone, a low-temperature coupling zone, and a dynamic quenching zone. The temperature of the photocatalytic zone is 35-45 °C, and an ultraviolet LED array with a wavelength of 360-370 nm is built-in; the temperature of the low-temperature coupling zone is -20 to -10 °C, temperature control is carried out by a semiconductor refrigeration module, and contact reaction is carried out through a static mixer; the temperature of the dynamic quenching zone is 0-5 °C, and the dynamic quenching zone is connected to a supercritical CO2 injection interface.

[0012] Preferably, in step S1, the ultraviolet light irradiation time is 30-90 seconds, and the light intensity is 50-100 mW / cm2.

[0013] Preferably, in step S1, the volume ratio of 5-bromo-2-chloro-4'-ethoxydiphenylmethane to THF is 1:3-5, and in step S2, the molar ratio of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone to 5-bromo-2-chloro-4'-ethoxydiphenylmethane is 1.05-1.15:1.

[0014] Preferably, in step S3, the operating conditions of supercritical CO2 are a pressure of 8-12 MPa, a temperature of 30-40 °C, the volume flow ratio of CO2 to the reaction solution is 5-10:1, and the product is separated by pressure reduction after extraction.

[0015] Preferably, the inner diameter of the channels of the microreactor is 0.5 - 1.0 mm, and the material is 316L stainless steel coated with a calcium fluoride coating on the surface. A spiral static mixer is installed in the low-temperature coupling zone.

[0016] Preferably, after step S3, the photocatalyst enters the separation kettle with CO2 and is recycled after pressure reduction and precipitation.

[0017] Preferably, in step S2, the residence time of the reaction solution in the low-temperature coupling zone is 2 - 5 minutes, and the flow rate is 0.5 - 2.0 mL / min.

[0018] In summary, compared with the prior art, the present invention has the following advantages:

[0019] 1. In the solution of the present invention, the temperature control of the microreactor in different zones (photocatalysis - low-temperature coupling - dynamic quenching) realizes rapid mass and heat transfer, continuous and efficient synthesis. The total reaction time is shortened to within 10 minutes, and the yield is increased to more than 90%.

[0020] 2. In the solution of the present invention, the palladium catalyst supported on carbon nitride is in-situ separated and recovered through a supercritical CO2 extraction system, forming a green catalyst cycle. The activity still remains above 95% after 5 cycles.

[0021] 3. In the solution of the present invention, the product purification is synchronously completed by supercritical CO2 dynamic quenching, avoiding the pollution of traditional quenching agents, achieving the effect of high-selectivity separation, and the product purity ≥ 99%.

[0022] 4. In the solution of the present invention, the optimization of the inner diameter of the microchannel and the design of the calcium fluoride coating inhibit side reactions, and the spiral mixer enhances the low-temperature coupling efficiency. With the advantages of equipment integration, the process stability is significantly improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the synthesis route of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0024] The technical solution of the present invention will be further specifically described below through specific examples, but the present invention is not limited to these examples.

[0025] Example 1

[0026] Step 1: Photocatalytic pre-activation

[0027] The starting material 5-bromo-2-chloro-4'-ethoxydiphenylmethane (8.1 g, 0.025 mol) and carbon nitride supported palladium nanoparticle complex (palladium loading 0.5 wt%, dosage 1.25 mmol) were added to 24 mL of THF solvent (the volume ratio of raw material to THF is 1:4). After mixing evenly, it was introduced into a UV photocatalytic microchannel (inner diameter 0.8 mm, made of 316L stainless steel with a calcium fluoride coating on the surface). The temperature of the photocatalytic zone was set at 40 °C, the wavelength of the UV light was 365 nm, the light intensity was 80 mW / cm2, and the irradiation time was 60 seconds to generate an aryl radical intermediate (pre-activated solution).

[0028] Step 2: Low-temperature coupling reaction

[0029] The pre-activated solution and the THF solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone (9 g, 0.0275 mol) were respectively pumped into the low-temperature coupling zone (-15 °C) of the microreactor at a flow rate of 1.2 mL / min. A spiral static mixer (number of mixing units 6) was installed in this area, and the reaction residence time was 3 minutes.

[0030] Step 3: Dynamic quenching and separation

[0031] The reaction solution entered the dynamic quenching zone (temperature 3 °C) and was mixed online with supercritical CO2 (pressure 10 MPa, temperature 35 °C) at a volume flow ratio of 8:1. The mixed solution entered the separation kettle (pressure reduced to atmospheric pressure). The precipitated crystals were collected and the photocatalyst was recovered through a filter membrane to obtain 9.39 g of intermediate I product. The purity analyzed by HPLC reached 99.2%, and the yield was 92%. The activity of the catalyst remained 96% after being recycled 5 times.

[0032] Example 2

[0033] Step 1: Photocatalytic pre-activation

[0034] The palladium loading of the photocatalyst was adjusted to 0.8 wt%, and the dosage was 0.8% of the molar amount of the raw material. The volume ratio of THF to the raw material was 1:3. The temperature of the photocatalytic zone was 35 °C, the wavelength of the UV light was 370 nm, the light intensity was 50 mW / cm2, and the irradiation time was 90 seconds. The other conditions were the same as in Example 1.

[0035] Step 2: Low-temperature coupling reaction

[0036] The molar ratio of the raw material to the sugar lactone was adjusted to 1:1.15. The temperature of the low-temperature coupling zone was -20 °C, the flow rate was 0.5 mL / min, and the residence time was 5 minutes.

[0037] Step 3: Dynamic quenching and separation

[0038] The pressure of supercritical CO2 is increased to 12 MPa, the volume flow ratio is 10:1, the purity of the separated product is 99.0%, and the yield is 89%. The activity of the catalyst is 94% after 5 cycles.

[0039] Example 3

[0040] Step 1: Photocatalytic pre-activation

[0041] A catalyst with a palladium loading of 0.3 wt% is used, and the amount is 0.3% of the molar amount of the raw material. The volume ratio of THF to the raw material is 1:5. The temperature in the photocatalytic zone is 45 °C, the wavelength of the ultraviolet light is 360 nm, the light intensity is 100 mW / cm2, and the irradiation time is 30 seconds.

[0042] Step 2: Low-temperature coupling reaction

[0043] The temperature in the low-temperature coupling zone is -10 °C, the flow rate is 2.0 mL / min, the residence time is 2 minutes, and the molar ratio of lactone is 1:1.05.

[0044] Step 3: Dynamic quenching and separation

[0045] The pressure of supercritical CO2 is 8 MPa, the volume flow ratio is 5:1, the purity of the product is 98.8%, and the yield is 90%. The activity of the catalyst is 93% after 5 cycles.

[0046] Comparative example

[0047] A traditional batch reactor is used instead of the microreactor. The photocatalytic step takes 30 minutes, the coupling reaction is carried out at -5 °C, and after quenching, it is purified by column chromatography. The purity of the final product is 97.5%, the yield is 78%, and the catalyst cannot be recovered.

[0048] Combining the data of Examples 1-3 and the comparative example, the following comparison results can be obtained:

[0049] 1. Reaction efficiency: The total reaction time of Example 1 of the present invention is ≤8 minutes, which is 75% shorter than that of the comparative example;

[0050] 2. Product purity: Supercritical CO2 dynamic extraction avoids the introduction of impurities, and the purity is increased by ≥1.5%;

[0051] 3. Catalyst recycling: The microreactor-supercritical system realizes efficient recovery of the catalyst, and the recycling loss rate is ≤2%;

[0052] 4. Energy consumption: The energy consumption of the continuous process is 40% lower than that of the batch process.

[0053] The embodiments of the present invention are not limited to those described in the above examples. Without departing from the spirit and scope of the present invention, those of ordinary skill in the art can make various changes and improvements in form and details, and all of these are considered to fall within the protection scope of the present invention.

Claims

1. A method for continuously synthesizing a dapagliflozin intermediate, characterized in that: The method comprises the following steps: S1: 5-bromo-2-chloro-4'-ethoxydiphenylmethane, a photocatalyst and THF are mixed and introduced into an ultraviolet photocatalytic microchannel for pre-activation to generate an aromatic free radical intermediate, i.e., a pre-activated solution; S2: contacting the pre-activated solution of step S1 with a THF solution of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone in a low-temperature coupling zone of a microreactor to obtain a reaction solution; S3: The reaction solution of step S2 is introduced into the dynamic quenching zone, mixed with supercritical CO2 online, and the intermediate I is obtained by supercritical fluid extraction and separation, and the photocatalyst is recovered.

2. The method for continuously synthesizing a dapagliflozin intermediate according to claim 1, characterized in that: The photocatalyst is a carbon nitride-supported palladium nanoparticle complex, wherein the supported amount of palladium is 0.1-1.0 wt %, and the amount of the photocatalyst is 0.1-1 % of the molar amount of 5-bromo-2-chloro-4'-ethoxydiphenylmethane.

3. The method for continuously synthesizing a dapagliflozin intermediate according to claim 1, characterized in that: The microreactor is divided into three independent temperature control zones, including a photocatalytic zone, a low-temperature coupling zone, and a dynamic quenching zone. The temperature of the photocatalytic zone is 35 to 45°C, and a built-in ultraviolet LED array with a wavelength of 360 to 370 nm is installed; the temperature of the low-temperature coupling zone is -20 to -10°C, and a semiconductor refrigeration module is used for temperature control, and a contact reaction is carried out through a static mixer; the temperature of the dynamic quenching zone is 0 to 5°C, and the dynamic quenching zone is connected to a supercritical CO2 injection interface.

4. The method for continuously synthesizing a dapagliflozin intermediate according to claim 1, characterized in that: In step S1, the ultraviolet light irradiation time is 30 to 90 seconds, and the light intensity is 50 to 100 mW / cm2.

5. The method for continuously synthesizing a dapagliflozin intermediate according to claim 1, characterized in that: The volume ratio of 5-bromo-2-chloro-4'-ethoxydiphenylmethane to THF in step S1 is 1:3-5, and the molar ratio of the 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone to the 5-bromo-2-chloro-4'-ethoxydiphenylmethane in step S2 is 1.05-1.15:

1.

6. The method for continuously synthesizing a dapagliflozin intermediate according to claim 1, characterized in that: The operating conditions of supercritical CO2 in step S3 are pressure 8-12 MPa, temperature 30-40°C, volume flow ratio of CO2 to reaction liquid 5-10:1, and the product is separated by reducing the pressure after extraction.

7. The method for continuously synthesizing a dapagliflozin intermediate according to claim 1, characterized in that: The inner diameter of the channel of the microreactor is 0.5-1.0 mm, the material is 316L stainless steel with a calcium fluoride coating on the surface, and a spiral static mixer is built in the low-temperature coupling zone.

8. The method for continuously synthesizing a dapagliflozin intermediate according to claim 1, characterized in that: The photocatalyst enters the separation kettle along with CO2 after step S3 and is recycled after being depressurized and precipitated.

9. The method for continuously synthesizing a dapagliflozin intermediate according to claim 1, characterized in that: In step S2, the residence time of the reaction solution in the low temperature coupling zone is 2 to 5 minutes, and the flow rate is 0.5 to 2.0 mL / min.

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