Production process and device for intermediate bromide of dapagliflozin

Abstract

The invention belongs to the technical field of medicine production, and particularly relates to a production process and device of dapagliflozin intermediate bromide, and the production process comprises the following steps: taking o-toluidine as a raw material, dissolving in N, N-dimethylformamide, introducing air and hydrobromic acid under the catalysis of supported noble metal, and distilling to obtain 4-bromo-2-methylaniline; mixing with acetic acid and acetic anhydride, adding amyl nitrite to prepare a diazonium salt solution, and reacting with copper powder and ammonium chloride to obtain 5-bromo-2-chlorotoluene; the preparation method comprises the following steps: mixing 5-bromo-2-chloro-4 '-ethyoxyl diphenylmethane with toluene, adding benzoyl peroxide and N-bromosuccinimide for treatment, and finally in dichloromethane, by taking phenetole as a raw material, carrying out solid acid catalysis and distillation purification to obtain 5-bromo-2-chloro-4'-ethyoxyl diphenylmethane. In early bromination, a supported noble metal catalyst is adopted, and air and hydrobromic acid react under mild conditions; the steps of diazonium salt preparation and chlorine atom introduction are simple, the operation complexity is reduced, N-bromo-diphenylmethane is used in benzyl halogenation, by-products are few, products are excellent, purification is easy, and environmental protection is good.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical production, and particularly relates to a production process and device for an intermediate bromide of dapagliflozin. Background Art

[0002] As a drug widely used in the treatment of type 2 diabetes, the unique mechanism of action of dapagliflozin is to inhibit sodium-glucose cotransporter 2 (SGLT2), reduce the reabsorption of glucose by the kidneys, thereby increasing urinary glucose excretion and lowering blood glucose levels. In the synthesis process of dapagliflozin, the preparation of the intermediate bromide 5-bromo-2-chloro-4'-ethoxydiphenylmethane plays a crucial role, and it is one of the key starting materials for constructing the molecular structure of dapagliflozin.

[0003] For example, Chinese Patent Application No. (2014106644657) discloses a preparation method of 5-bromo-2-chloro-4'-ethoxydiphenylmethane. The preparation method adopted in this application has multiple complex reactions, such as bromination reaction, Sandmeyer reaction, and Friedel-Crafts alkylation reaction, etc., all of which require specific and relatively strict reaction conditions, and there are many by-products. The process of product separation and purification is complex, and a large amount of separation reagents and equipment are required, increasing the production cost and time cost. Summary of the Invention

[0004] The object of the present invention is to address the above-mentioned existing technical problems, and provide a production process and device for an intermediate bromide of dapagliflozin, achieving the effect of reacting under relatively mild conditions, reducing the generation of by-products, and facilitating the separation and purification of products.

[0005] In view of this, the present invention provides a production process for an intermediate bromide of dapagliflozin, including the following steps:

[0006] S1: Dissolve o-toluidine in N,N-dimethylformamide at a mass ratio of 1:3 - 10;

[0007] S2: Add a supported noble metal catalyst, and under room temperature conditions, introduce air and slowly dropwise add hydrobromic acid, and react for 3 - 4 h;

[0008] S3: Under the conditions of a pressure of 10 - 20 mmHg and a temperature of 60 - 80 °C, remove N,N-dimethylformamide and unreacted raw materials by vacuum distillation to obtain 4-bromo-2-methylaniline;

[0009] S4: Mix the 4-bromo-2-methylaniline in S3 with a mixed solution of acetic acid and acetic anhydride at a mass ratio of 1:2 - 6 and dissolve it;

[0010] S5: Slowly add amyl nitrite at a temperature of 0 - 5 °C, and maintain stirring reaction at 0 - 5 °C for 30 min to obtain a diazonium salt solution;

[0011] S6: Add a mixture of copper powder and ammonium chloride with a molar ratio of 1:2. After reacting at room temperature for 2 - 3 h, remove the solid matter by filtration, and distill and purify the filtrate to obtain 5 - bromo - 2 - chlorotoluene;

[0012] S7: Mix 5 - bromo - 2 - chlorotoluene in S6 and toluene at a mass ratio of 1:3 - 8 to dissolve it;

[0013] S8: Add benzoyl peroxide, and after heating to 110 °C, slowly add N - bromosuccinimide. After reacting for 2 - 3 h, filter to remove the generated succinimide, and distill and purify the filtrate to obtain a benzylic halogenated compound;

[0014] S9: Add the benzylic halogenated compound and phenetole to a reaction kettle containing dichloromethane at a molar ratio of 1:1.05 - 1.4. Add a solid acid catalyst, and after reacting at room temperature for 4 - 5 h, filter to remove the catalyst, and distill and purify the filtrate to obtain the intermediate bromide of dapagliflozin, 5 - bromo - 2 - chloro - 4'-ethoxydiphenylmethane.

[0015] In the above technical solution, further:

[0016] In S2, the molar ratio of o - toluidine to hydrobromic acid is 1:1.1 - 1.6, and the supported noble metal catalyst can be one of a palladium catalyst supported on activated carbon, a platinum catalyst supported on titanium dioxide, and a gold catalyst supported on carbon nanotubes.

[0017] In the above technical solution, further:

[0018] In S5, the molar ratio of 4 - bromo - 2 - methylaniline to amyl nitrite is 1:1.05 - 1.4.

[0019] In the above technical solution, further:

[0020] In S6, the molar ratio of the diazonium salt to copper powder is 1:0.7 - 1.3.

[0021] In the above technical solution, further:

[0022] In S8, benzoyl peroxide accounts for 0.5% - 5% of 5 - bromo - 2 - chlorotoluene, and the molar ratio of 5 - bromo - 2 - chlorotoluene to N - bromosuccinimide is 1:1.05 - 1.35.

[0023] In the above technical solution, further:

[0024] In S9, the solid acid catalyst accounts for 2%-6% of the mass of the benzylic halogenated compound, and the solid acid catalyst can be one of solid superacids, supported heteropolyacid catalysts, and sulfonated mesoporous carbon materials.

[0025] The present invention provides a production device for a production process of a brominated intermediate of dapagliflozin, comprising:

[0026] A reaction kettle, which is internally provided with a reaction chamber and a distillation chamber located below the reaction chamber;

[0027] A filtering component, which is installed between the reaction chamber and the distillation chamber and is used for filtering the solution entering the distillation chamber from the reaction chamber;

[0028] A blocking component, which is installed below the filtering component and is used for separating the reaction chamber from the distillation chamber, and comprises a driving unit for switching between the communication and separation of the reaction chamber and the distillation chamber;

[0029] A stirring component, which is installed in the reaction chamber and is used for stirring during the reaction, and comprises a cleaning unit for cleaning the filtering component;

[0030] A condensing component, which is installed on the side of the reaction kettle and is connected to the distillation chamber;

[0031] Among them, the reaction kettle is provided with a feeding port, a feeding inlet, and a cleaning outlet on the reaction chamber, and a discharging outlet, a gas outlet, and a cleaning inlet on the distillation chamber.

[0032] In the above technical solution, further, the filtering component comprises:

[0033] A filter screen, which is installed on the inner wall of the reaction kettle through a fixed ring and is located between the reaction chamber and the distillation chamber;

[0034] Support rods, which are circumferentially arranged in plurality on one side of the fixed ring close to the axis and are located below the filter screen, and a liquid passing port is formed between two adjacent support rods.

[0035] In the above technical solution, further, it is characterized in that the blocking component comprises:

[0036] A disc, which is installed below the support rod and forms a liquid passing channel with the inner wall of the reaction kettle;

[0037] Among them, the driving unit comprises:

[0038] A cylinder body, which is installed on the bottom wall of the distillation chamber and is provided with a cover on the upper end surface;

[0039] A piston body, which is slidably connected in the cylinder body, and a top column is arranged on one side close to the cover and penetrates through the cover and is connected to the disc;

[0040] The gas injection pipe, an air injection port is provided on the bottom wall of the distillation chamber and is respectively connected to the inside of the cylinder body and the gas injection pipe;

[0041] The air release pipe, an air release port is provided on the bottom wall of the distillation chamber and is respectively connected to the inside of the cylinder body and the air release pipe;

[0042] The valve body is installed below the reaction kettle and is respectively provided with a first channel and a second channel communicated with the gas injection pipe and the air release pipe;

[0043] The valve core is installed in the valve body and is provided with a first through hole communicated with the first channel and a second through hole communicated with the second channel, and the axes of the first through hole and the second through hole are vertically arranged;

[0044] The first driving motor is installed on the side of the valve body and is used to drive the valve core to rotate to alternately conduct the first channel and the second channel;

[0045] Among them, the gas injection pipe is connected with a gas supply unit.

[0046] In the above technical solution, further, the stirring assembly includes:

[0047] The main shaft is vertically installed in the reaction chamber, and one end extends out of the reaction kettle and is provided with a second driving motor;

[0048] The stirring rod is installed on the surface of the main shaft located in the reaction chamber;

[0049] Among them, the cleaning unit includes:

[0050] The fixed block is installed at one end of the main shaft close to the filter screen;

[0051] One end of the rotating shaft is connected to the fixed block by a bearing and is arranged parallel to the radial surface of the filter screen;

[0052] The gear is installed at the end of the rotating shaft away from the fixed block;

[0053] The annular rack is installed on the fixed ring and meshes with the gear;

[0054] The rubber blade is installed on the surface of the rotating shaft, and one side is in contact with the surface of the filter screen;

[0055] Among them, when the rubber blade is close to the filter screen, it can be bent under the influence of the solution, and a diversion gap is formed between the bent rubber blade and the surface of the filter screen.

[0056] The beneficial effects of the present invention are:

[0057] 1. In the early bromination step, the supported noble metal catalyst, air and hydrobromic acid are used under relatively mild conditions. The subsequent methods for preparing the diazonium salt and introducing chlorine atoms are also more concise, reducing the reaction steps, the operation complexity and the production cycle.

[0058] 2. N-bromo-diphenylmethane used in benzylic halogenation has relatively little impact on by-products in its process system. The selectivity and purity of the product are easier to ensure, and the separation and purification are relatively simple. The types and quantities of by-products are relatively small, and the pressure of treating the three wastes is relatively small, making it more environmentally friendly.

[0059] 3. By adopting an integrated structure of reaction, filtration, and distillation, the removal of by-products and distillation purification in steps S6, S8, and S9 are carried out, avoiding the transfer of materials between different devices, thus avoiding the pollution of materials and the environment. In terms of product quality, the purity and stability of the product are significantly improved; in terms of environmental protection, the pressure of environmental pollution is greatly reduced, strongly promoting the process of green production. Brief Description of the Drawings

[0060] Figure 1 is a schematic structural diagram of the production device of the present invention;

[0061] Figure 2 is a top view of the production device of the present invention;

[0062] Figure 3 is the present invention Figure 2 a cross-sectional view taken along line A-A in;

[0063] Figure 4 is the present invention Figure 3 an enlarged view of part B in;

[0064] Figure 5 is the present invention Figure 3 an enlarged view of part C in;

[0065] Figure 6 is a schematic internal structure diagram of the production device of the present invention;

[0066] The reference numerals in the drawings are represented as: 1, reaction kettle; 2, reaction chamber; 3, distillation chamber; 4, filtration assembly; 40, filter mesh; 41, fixing ring; 42, support rod; 43, liquid passing port; 5, plugging assembly; 50, disc; 51, liquid passing channel; 6, driving unit; 60, cylinder body; 61, cover; 62, piston body; 63, top column; 64, injection pipe; 640, injection port; 65, exhaust pipe; 650, exhaust port; 66, valve body; 660, first channel; 661, second channel; 67, valve core; 670, first through hole; 671, second through hole; 68, first driving motor; 7, stirring assembly; 70, main shaft; 71, second driving motor; 72, stirring rod; 8, cleaning unit; 80, fixing block; 81, rotating shaft; 82, gear; 83, annular rack; 84, rubber blade; 9, jacket assembly; 10, feeding port; 11, inlet; 12, cleaning outlet; 13, outlet; 14, gas outlet; 15, cleaning inlet; 16, reflux port. Detailed implementation mode

[0067] Next, the technical solutions in the embodiments of the present application will be clearly described in conjunction with the accompanying drawings in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art belong to the scope protected by the present application.

[0068] Embodiment 1:

[0069] This embodiment provides a production process for an intermediate bromide of dapagliflozin, including the following steps:

[0070] S1: Dissolve o-toluidine in N,N-dimethylformamide at a mass ratio of 1:6;

[0071] S2: Add a supported noble metal catalyst, and at room temperature of 25 °C, introduce air, and slowly drip hydrobromic acid through a metering pump, and react for 3.5 h;

[0072] S3: Under the conditions of a pressure of 15 mmHg and a temperature of 70 °C, remove N,N-dimethylformamide and unreacted raw materials by vacuum distillation to obtain 4-bromo-2-methylaniline;

[0073] S4: Mix the 4-bromo-2-methylaniline in S3 with a mixed solution of acetic acid and acetic anhydride at a mass ratio of 1:4 to dissolve it;

[0074] S5: Cool down to a temperature of 3 °C, slowly drip amyl nitrite through a metering pump, and keep stirring and reacting at 3 °C for 30 min to obtain a diazonium salt solution;

[0075] S6: Add a mixture of copper powder and ammonium chloride with a molar ratio of 1:2, react at room temperature of 25 °C for 2.5 h, then filter to remove solids, and distill and purify the filtrate to obtain 5-bromo-2-chlorotoluene;

[0076] S7: Mix the 5-bromo-2-chlorotoluene in S6 with toluene at a mass ratio of 1:5 to dissolve it;

[0077] S8: Add benzoyl peroxide, heat up to 110 °C, then slowly drip N-bromosuccinimide through a metering pump, react for 2.5 h, filter to remove the generated succinimide, and distill and purify the filtrate to obtain a benzylic halogenated compound;

[0078] S9: Add the benzylic halogenated compound and phenetole into a reaction kettle containing dichloromethane at a molar ratio of 1:1.2. Add a solid acid catalyst and react at room temperature for 4.5 h. Then filter out the catalyst and distill and purify the filtrate to obtain the intermediate bromide of dapagliflozin, 5-bromo-2-chloro-4'-ethoxydiphenylmethane;

[0079] Among them, in S2, the molar ratio of o-toluidine to hydrobromic acid is 1:1.3, and the supported noble metal catalyst is a palladium catalyst supported on activated carbon;

[0080] In the mixed solution of acetic acid and acetic anhydride in S4, the volume ratio of acetic acid to acetic anhydride is 3:1;

[0081] In S5, the molar ratio of 4-bromo-2-methylaniline to amyl nitrite is 1:1.2;

[0082] In S6, control the molar ratio of diazonium salt to copper powder to be 1:1;

[0083] In S8, benzoyl peroxide accounts for 2% of 5-bromo-2-chlorotoluene, and the molar ratio of 5-bromo-2-chlorotoluene to N-bromosuccinimide is 1:1.2;

[0084] In S9, the solid acid catalyst accounts for 4% of the mass of the benzylic halogenated compound, and the solid acid catalyst is a solid superacid.

[0085] It can be seen from this example that in the early bromination step, a supported noble metal catalyst, air and hydrobromic acid are used to carry out the reaction under relatively mild conditions. The subsequent methods for preparing diazonium salt and introducing chlorine atoms are also more concise, reducing the reaction steps, lowering the operation complexity and production cycle;

[0086] N-bromo-diphenylmethane used in benzylic halogenation has relatively little influence on by-products in its process system. The selectivity and purity of the product are more easily guaranteed, and the separation and purification are relatively simple. The types and quantities of by-products are relatively small, and the pressure of three-waste treatment is relatively small, showing more advantages in environmental protection.

[0087] Example 2:

[0088] This example provides a production device for the production process of the intermediate bromide of dapagliflozin, including:

[0089] A reaction kettle 1, internally provided with a reaction chamber 2 and a distillation chamber 3 located below the reaction chamber 2;

[0090] A filtering component 4, installed between the reaction chamber 2 and the distillation chamber 3 and used for filtering the solution entering the distillation chamber 3 from the reaction chamber 2;

[0091] The plugging assembly 5 is installed below the filtering assembly 4 and is used to separate the reaction chamber 2 from the distillation chamber 3, and includes a driving unit 6 for switching the reaction chamber 2 and the distillation chamber 3 between connection and separation;

[0092] A stirring assembly 7 is installed in the reaction chamber 2 and is used for stirring during the reaction, and includes a cleaning unit 8 for cleaning the filter assembly 4;

[0093] A jacket assembly 9 is sleeved on the surface of the reaction kettle 1 and is used for adjusting the temperature in the reaction chamber 2 and the distillation chamber 3 respectively;

[0094] A condensation assembly is installed on the side of the reaction kettle 1 and connected to the distillation chamber 3;

[0095] The reactor 1 is provided with a feeding port 10, a feed port 11 and a cleaning port 12 on the reaction chamber 2, and a discharge port 13, a gas outlet 14, a cleaning port 15 and a reflux port 16 on the distillation chamber 3;

[0096] Meanwhile, the condensation component is a condenser, which is connected to the gas outlet 14 and the reflux port 16. The specific structure of the condenser and the jacket component 9 is an existing mature technology, which is known to technicians in the relevant technical field from the traditional condenser, and will not be repeated here;

[0097] Furthermore, the feed port 11 is connected to a metering pump.

[0098] It can be seen from the present embodiment that by adopting an integrated structure of reaction, filtration and distillation, the by-products of steps S6, S8 and S9 are removed and purified by distillation, thereby avoiding the transfer of materials between different equipment and the pollution of materials and the environment. In terms of product quality, the purity and stability of the product are significantly improved; in terms of environmental protection, the pressure of environmental pollution is greatly reduced, and the green production process is strongly promoted.

[0099] Embodiment 3:

[0100] This embodiment provides a production device for the production process of an intermediate bromide of dapagliflozin, which, in addition to the technical solutions of the above embodiments, also has the following technical features: the filter component 4 includes:

[0101] The filter screen 40 is installed on the inner wall of the reaction kettle 1 by means of a fixing ring 41 and is located between the reaction chamber 2 and the distillation chamber 3;

[0102] A plurality of support rods 42 are provided on a circumference of one side of the fixing ring 41 close to the axis and are located below the filter screen 40 , and a liquid passage 43 is formed between two adjacent support rods 42 .

[0103] As can be seen from this embodiment, the structural strength of the filter net 40 can be improved through the support rod 42. When reacting on the material, excessive deformation of the filter net 40 can be avoided. The liquid passing openings 43 formed between two adjacent support rods 42 can ensure the filtration of the material when the reaction chamber 2 and the distillation chamber 3 are communicated.

[0104] Embodiment 4:

[0105] This embodiment provides a production device for the production process of the intermediate bromide of dapagliflozin. In addition to including the technical solutions of the above embodiments, it also has the following technical features. The blocking component 5 includes:

[0106] A disc 50, installed below the support rod 42 and forming a liquid passing channel 51 between the inner wall of the reaction kettle 1;

[0107] Among them, the driving unit 6 includes:

[0108] A cylinder body 60, installed on the bottom wall of the distillation chamber 3, and a cover 61 is provided on the upper end surface;

[0109] A piston body 62, slidably connected inside the cylinder body 60, and a top column 63 is provided on the side close to the cover 61. After passing through the cover 61, it is connected to the disc 50;

[0110] An air injection pipe 64, an air injection port 640 is opened on the bottom wall of the distillation chamber 3 and is respectively connected to the inside of the cylinder body 60 and the air injection pipe 64;

[0111] An air discharge pipe 65, an air discharge port 650 is opened on the bottom wall of the distillation chamber 3 and is respectively connected to the inside of the cylinder body 60 and the air discharge pipe 65;

[0112] A valve body 66, installed below the reaction kettle 1, and respectively provided with a first channel 660 and a second channel 661 communicated with the air injection pipe 64 and the air discharge pipe 65;

[0113] A valve core 67, installed inside the valve body 66, and provided with a first through hole 670 communicated with the first channel 660 and a second through hole 671 communicated with the second channel 661, and the axes of the first through hole 670 and the second through hole 671 are vertically arranged;

[0114] A first driving motor 68, installed on the side of the valve body 66, and used to drive the valve core 67 to rotate to alternately communicate the first channel 660 and the second channel 661;

[0115] Among them, the air injection pipe 64 is connected with a gas supply unit. The gas supply unit can adopt an air compressor, and the air discharge pipe 65 can be directly connected to the outside;

[0116] At the same time, the first driving motor 68 is a traditional motor, and its specific structure is the prior art, which will not be elaborated here.

[0117] As can be seen from this embodiment, by installing the disc 50 below the support rod 42, the structural strength can be further improved. During the reaction of the material, the material is supported to prevent excessive deformation of the filter screen 40.

[0118] And an air compressor is used to push the piston, and then the disc 50 is pushed to abut against the fixed ring 41, thereby sealing between the reaction chamber 2 and the distillation chamber 3 to ensure the reaction of the material.

[0119] Meanwhile, by using the first drive motor 68 to drive the valve core 67 to rotate, the first through hole 670 and the second through hole 671 in the valve core 67 are alternately communicated with the injection pipe 64 and the drain pipe 65, which is convenient for controlling the piston, and then it is convenient to switch between the communication and separation of the reaction chamber 2 and the distillation chamber 3. Specifically, when the injection pipe is communicated with the air supply unit, the valve core 67 on the drain pipe 65 is in a closed state, and the air pressure in the air supply unit will push the piston and then push the disc 50 to separate the reaction chamber 2 and the distillation chamber 3. When the valve core 67 of the injection pipe is in a closed state, it is cut off from the air supply unit, and the valve core 67 on the drain pipe 65 is in an open state and communicated with the outside, and the high pressure in the cylinder body 60 is discharged. Then, under the action of the gravity of the material, the disc 50 is pressed down, and the material enters the distillation chamber 3 from the reaction chamber 2 through the holes of the filter screen 40, the liquid passing port 43 and the liquid passing channel 51 in sequence.

[0120] Embodiment 5:

[0121] This embodiment provides a production device for the production process of the intermediate bromide of dapagliflozin. In addition to including the technical solutions of the above embodiments, it also has the following technical features. The stirring assembly 7 includes:

[0122] The main shaft 70 is vertically installed in the reaction chamber 2, and one end extends out of the reaction kettle 1 and is provided with a second drive motor 71.

[0123] The stirring rod 72 is installed on the surface of the main shaft 70 located in the reaction chamber 2.

[0124] Among them, the cleaning unit 8 includes:

[0125] The fixed block 80 is installed at one end of the main shaft 70 close to the filter screen 40.

[0126] One end of the rotating shaft 81 is connected to the fixed block 80 by a bearing and is arranged parallel to the radial surface of the filter screen 40.

[0127] The gear 82 is installed at the end of the rotating shaft 81 far from the fixed block 80.

[0128] The annular rack 83 is installed on the fixed ring 41 and meshes with the gear 82.

[0129] The rubber blade 84 is installed on the surface of the rotating shaft 81 and contacts the surface of the filter screen 40 on one side;

[0130] Among them, when the rubber blade 84 is close to the filter screen 40, it can be bent under the influence of the solution, and a diversion gap is formed between the bent rubber blade 84 and the surface of the filter screen 40.

[0131] It can be seen from this embodiment that by arranging the cleaning unit 8 in the stirring assembly 7, it is possible to avoid large-area deposition of materials on the filter screen 40 during the stirring of the material reaction, which affects the filtration efficiency. Specifically, while the rotating shaft 81 rotates following the rotating shaft 81, it can rotate self-driven under the action of the gear 82 and the annular rack 83, and then the rubber blade 84 is used to clean the deposits on the surface of the filter screen 40 to ensure the filtration efficiency;

[0132] And when the rubber blade 84 is cleaning, it can be bent under the influence of the resistance of the liquid, so that the cleaning of the surface of the filter screen 40 by the rubber blade 84 drives the solution to flow, and then drives the deposits on the surface of the filter screen 40 to move along with it, which can avoid the direct contact between the rubber blade 84 and the filter screen 40, reduce the damage caused by direct contact with the filter screen 40, extend the service life of the filter screen 40, and when the solution is less, the rotation of the rubber blade 84 no longer generates fluid flow, and the rubber blade 84 no longer receives a large liquid resistance, the rubber blade 84 will stick to the surface of the filter screen 40 to remove the deposits, which can effectively ensure the filtration effect.

[0133] The embodiments of the present application have been described above in conjunction with the accompanying drawings. Without conflict, the embodiments and features in the embodiments of the present application can be combined with each other. The present application is not limited to the above specific embodiments. The above specific embodiments are only illustrative and not restrictive. Under the inspiration of the present application, those of ordinary skill in the art can also make many forms without departing from the purpose of the present application and the scope protected by the claims, and all belong to the protection scope of the present application.

Claims

1. A process for producing an intermediate bromide of dapagliflozin, characterized in that: The following steps are involved: S1: dissolving o-toluidine in N,N-dimethylformamide at a mass ratio of 1:3-10; S2: Add a supported noble metal catalyst, introduce air at room temperature, and slowly drop hydrobromic acid for 3-4 hours; S3: removing N,N-dimethylformamide and unreacted raw materials by reduced pressure distillation at a pressure of 10-20 mmHg and a temperature of 60-80° C. to obtain 4-bromo-2-methylaniline; S4: mixing the 4-bromo-2-methylaniline in S3 with the mixed solution of acetic acid and acetic anhydride in a mass ratio of 1:2-6 to dissolve them; S5: slowly add amyl nitrite dropwise at a temperature of 0-5°C, and stir the reaction at 0-5°C for 30 minutes to obtain a diazonium salt solution; S6: adding a mixture of copper powder and ammonium chloride in a molar ratio of 1:2, reacting at room temperature for 2 h-3 h, removing solids by filtration, and distilling and purifying the filtrate to obtain 5-bromo-2-chlorotoluene; S7: Mix the 5-bromo-2-chlorotoluene and toluene in S6 at a mass ratio of 1:3-8 to dissolve them; S8: Add benzoyl peroxide, raise the temperature to 110°C, slowly dropwise add N-bromosuccinimide, react for 2-3 hours, filter to remove the generated succinimide, and purify the filtrate by distillation to obtain a benzyl halogenated compound; S9: Add the benzyl halogenated compound and phenethyl ether in a molar ratio of 1:1.05-1.4 into a reaction kettle containing dichloromethane, add a solid acid catalyst, react at room temperature for 4-5 hours, filter out the catalyst, and purify the filtrate by distillation to obtain the intermediate bromide of dapagliflozin 5-bromo-2-chloro-4'-ethoxydiphenylmethane.

2. The production process of the intermediate bromide of dapagliflozin according to claim 1, characterized in that: The molar ratio of o-toluidine to hydrobromic acid in S2 is 1:1.1-1.6, and the supported noble metal catalyst can be one of an activated carbon-supported palladium catalyst, a titanium dioxide-supported platinum catalyst, and a carbon nanotube-supported gold catalyst.

3. The production process of the intermediate bromide of dapagliflozin according to claim 1, characterized in that: The molar ratio of 4-bromo-2-methylaniline to amyl nitrite in S5 is 1:1.05-1.

4.

4. The production process of the intermediate bromide of dapagliflozin according to claim 1, characterized in that: In S6, the molar ratio of diazonium salt to copper powder is controlled to be 1:0.7-1.

3.

5. The production process of the intermediate bromide of dapagliflozin according to claim 1, characterized in that: In S8, benzoyl peroxide accounts for 0.5%-5% of 5-bromo-2-chlorotoluene, and the molar ratio of 5-bromo-2-chlorotoluene to N-bromosuccinimide is 1:1.05-1.

35.

6. The production process of the intermediate bromide of dapagliflozin according to claim 1, characterized in that: In S9, the solid acid catalyst accounts for 2%-6% of the mass of the benzylic halogenated compound, and the solid acid catalyst can be one of a solid superacid, a supported heteropolyacid catalyst and a sulfonated mesoporous carbon material.

7. A production device for the production process of the intermediate brominated product of dapagliflozin according to any one of claims 1 to 6, characterized in that: include: A reaction kettle (1) is provided with a reaction chamber (2) and a distillation chamber (3) located below the reaction chamber (2); A filter assembly (4) is installed between the reaction chamber (2) and the distillation chamber (3) and is used to filter the solution entering the distillation chamber (3) from the reaction chamber (2); A plugging assembly (5) is installed below the filtering assembly (4) and is used to isolate the reaction chamber (2) and the distillation chamber (3), and includes a driving unit (6) for switching the reaction chamber (2) and the distillation chamber (3) between connection and isolation; A stirring assembly (7) is installed in the reaction chamber (2) and is used for stirring during the reaction, and includes a cleaning unit (8) for cleaning the filter assembly (4); A jacket assembly (9) is sleeved on the surface of the reaction kettle (1) and is used for regulating the temperature in the reaction chamber (2) and the distillation chamber (3); A condensation assembly is installed on the side of the reaction kettle (1) and is connected to the distillation chamber (3); The reactor (1) is provided with a feeding port (10), a feed port (11) and a cleaning outlet (12) on the reaction chamber (2), and is provided with a discharge port (13), a gas outlet (14) and a cleaning inlet (15) on the distillation chamber (3).

8. The production device of the production process of the intermediate bromide of dapagliflozin according to claim 7, characterized in that: The filter assembly (4) comprises: The filter screen (40) is installed on the inner wall of the reaction kettle (1) by means of a fixing ring (41) and is located between the reaction chamber (2) and the distillation chamber (3); A plurality of support rods (42) are arranged on a circumference of one side of the fixing ring (41) close to the axis and are located below the filter screen (40), and a liquid passage (43) is formed between two adjacent support rods (42).

9. The production device of the production process of the intermediate bromide of dapagliflozin according to claim 8, characterized in that: The blocking component (5) comprises: The disc (50) is installed below the support rod (42) and forms a liquid passage (51) with the inner wall of the reaction kettle (1); Wherein, the driving unit (6) comprises: A cylinder (60) is mounted on the bottom wall of the distillation chamber (3) and has a sealing cover (61) on its upper end surface; The piston body (62) is slidably connected in the cylinder body (60), and a top column (63) is provided on the side close to the sealing cover (61) and penetrates the sealing cover (61) and is connected to the disc (50); An air injection pipe (64), a bottom wall of the distillation chamber (3) is provided with an air injection port (640) which is respectively connected to the inside of the cylinder (60) and the air injection pipe (64); A vent pipe (65), a vent port (650) is provided on the bottom wall of the distillation chamber (3) and is respectively connected to the inside of the cylinder (60) and the vent pipe (65); A valve body (66) is installed below the reaction kettle (1) and is provided with a first channel (660) and a second channel (661) which are communicated with the gas injection pipe (64) and the gas release pipe (65) respectively; The valve core (67) is installed in the valve body (66) and is provided with a first through hole (670) and a second through hole (671) respectively connected to the first channel (660) and the second channel (661), and the axes of the first through hole (670) and the second through hole (671) are arranged perpendicularly; A first driving motor (68) is installed on the side of the valve body (66) and is used to drive the valve core (67) to rotate to alternately open the first channel (660) and the second channel (661); Wherein, the gas injection pipe (64) is connected to a gas supply unit.

10. The production device of the production process of the intermediate brominated product of dapagliflozin according to claim 8, characterized in that: The stirring assembly (7) comprises: A main shaft (70) is vertically mounted in the reaction chamber (2), and one end of the main shaft extends out of the reaction kettle (1) and is provided with a second driving motor (71); A stirring rod (72) is mounted on the surface of the main shaft (70) located inside the reaction chamber (2); Wherein, the cleaning unit (8) comprises: A fixed block (80) is mounted on one end of the main shaft (70) close to the filter screen (40); A rotating shaft (81), one end of which is connected to the bearing of the fixed block (80) and is arranged parallel to the radial surface of the filter screen (40); A gear (82) is mounted on an end of the rotating shaft (81) away from the fixed block (80); An annular rack (83) is mounted on the fixed ring (41) and meshes with the gear (82); A rubber blade (84) is mounted on the surface of the rotating shaft (81) and has one side in contact with the surface of the filter screen (40); Wherein, the rubber blade (84) can bend under the influence of the solution when it is close to the filter screen (40), and form a flow guide gap with the surface of the filter screen (40) after bending.

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