Preparation method of sitagliptin base

Abstract

The invention discloses a preparation method of sitagliptin base, and relates to the technical field of compound preparation, and the preparation method comprises the following steps: S1, adding 75 parts of water and 16 parts of hydrochloric acid into a three-neck bottle, and cooling to 0 DEG C; s2, the pH is adjusted to 7.5, 42.5 parts of a triethanolamine solution, 0.2 part of pyridoxal phosphate and 57 parts of DMSO are added, and the temperature is controlled to be lower than 10 DEG C; s3, adjusting the pH value to 8.5, adding 40 parts of liquid transaminase, and slowly heating to 40-45 DEG C; s4, when the temperature rises to 45 DEG C, 20 parts of diketone is dropwise added, the temperature is controlled to be 45 DEG C, the pH is adjusted to 8.5, and heat preservation is conducted for 24 h; s5, performing suction filtration and extraction, cooling and crystallizing through methyl tert-butyl ether to obtain a white solid, and drying to obtain a finished product sitagliptin base; preparation equipment adopted in the preparation method comprises a closed cylinder, a liquid separation mechanism, an organic phase receiving box, a water phase receiving box and the like, closed control in the liquid separation extraction process is achieved, recycling of the extraction agent is achieved, and the volatilization and dissipation amount of the extraction agent in the preparation process is effectively reduced.

Description

Technical Field

[0001] This invention relates to the field of compound preparation technology, specifically a method for preparing sitagliptin alkaloid. Background Technology

[0002] Sitagliptin is an active pharmaceutical ingredient with important applications in the pharmaceutical field, primarily used in the preparation of sitagliptin-related formulations, the most common being sitagliptin phosphate. Clinically, it is mainly used to treat type 2 diabetes. It can be used alone or in combination with other antidiabetic drugs such as metformin, thiazolidinediones, and sulfonylureas for better blood glucose control. Compared to other hypoglycemic drugs, sitagliptin has a lower risk of hypoglycemia and less impact on weight.

[0003] The preparation of sitagliptin requires separation using extraction technology, typically with dichloromethane. Dichloromethane is volatile under normal temperature and pressure, and it is harmful to human health. Furthermore, after extraction, the organic phase needs to be rotary dried to separate sitagliptin from dichloromethane. Throughout the extraction process, dichloromethane volatilizes and evaporates, easily causing it to escape into the air, polluting the working environment and posing a significant health hazard to the operators. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing sitagliptin to solve the problems mentioned in the background art.

[0005] To achieve the above objectives, the present invention provides the following technical solution: A method for preparing sitagliptin, The process includes the following steps: S1, adding 75 parts water and 16 parts hydrochloric acid to a three-necked flask and cooling to 0℃; S2, adjusting the pH of the three-necked flask to 7.5 by adding isopropylamine, adding 42.5 parts triethanolamine solution, adding 0.2 parts pyridoxal phosphate, and 57 parts DMSO, and controlling the temperature below 10℃; S3, adjusting the pH of the three-necked flask to 8.5 by adding isopropylamine, adding 40 parts liquid transaminase, and slowly raising the temperature to 40-45℃; S4, when the temperature reaches 45℃, adding 20 parts diketone, controlling the temperature at 45℃, adding isopropylamine to adjust the pH to 8.5, and maintaining the temperature for 24 hours; S5, filtering and extracting, cooling and crystallizing with methyl tert-butyl ether to obtain a white solid, drying to obtain the finished product sitagliptin.

[0006] A three-necked flask is placed on an operating table. A sealed cylinder is installed on the operating table, and a vacuum pump is connected to the sealed cylinder. The vacuum pump is connected to a vacuum tube, which extends to the bottom of the three-necked flask. A liquid separation mechanism is installed inside the sealed cylinder, which includes a liquid separation funnel and an extractant cylinder. An organic phase receiving box and an aqueous phase receiving box are installed on the operating table at the bottom of the sealed cylinder. The organic phase receiving box and the aqueous phase receiving box are connected to a drive assembly. The organic phase receiving box and the aqueous phase receiving box are respectively connected to the liquid separation funnel through the drive assembly to complete the reception of the organic phase and aqueous phase after liquid separation by the liquid separation mechanism. A cooling water tank is also included, which is connected to the extractant cylinder. The cooling water tank lowers the temperature of the connection channel between the organic phase receiving box and the extractant cylinder, condensing and liquefying the extractant vapor generated by heating and drying the organic phase and recovering it into the extractant cylinder.

[0007] As a further embodiment of the present invention: the separation mechanism also includes a connecting pipe 1 and a connecting pipe 2 connected to the top stopper of the separation funnel. The connecting pipe 1 is connected to the vacuum filtration pump. A fixing frame is provided between the extractant cylinder and the separation funnel. The fixing frame is fixedly connected to the side wall of the closed cylinder. A piston is provided inside the extractant cylinder. The piston is connected to a control column. The top of the extractant cylinder is connected to an addition pipe 2. The control column passes through the top of the addition pipe 2 and is inserted between the addition pipe 2 and the addition pipe 2. A branch pipe is provided at the top edge of the addition pipe 2. The top of the closed cylinder is also provided with an addition pipe 1. The addition pipe 1 and the addition pipe 2 are respectively connected to the connecting pipe 2.

[0008] As a further embodiment of the present invention: the height of the connection between the second added tube and the second connecting tube is higher than the height of the connection between the first added tube and the second connecting tube.

[0009] As a further embodiment of the present invention: an evaporator tube is provided on the side wall of the organic phase receiving box, and a control motor is provided on the side wall of the sealed cylinder corresponding to the position of the evaporator tube. The control motor is connected to a connector, which is set at a right angle. One end of the connector is mated with the evaporator tube, and the other end of the connector is connected to a telescopic tube. A gas guide pipe is fixedly installed on the inner wall of the sealed cylinder, and a gas pump is provided on the gas guide pipe. The gas guide pipe extends to the upper side of the sealed cylinder, and a spiral tube is provided on the upper side of the sealed cylinder. The gas guide pipe is arranged along the inside of the spiral tube and communicates with the lower end of the second adding pipe. The spiral tube is connected to a cooling water tank.

[0010] As a further embodiment of the present invention: the upper end of the spiral tube extends out of the closed cylinder and is connected to a water inlet pipe, the lower end of the spiral tube extends out of the closed cylinder and is connected to a water return pipe, the water inlet pipe and the water return pipe are respectively connected to the cooling water tank, and the portion of the air guide pipe between the telescopic tube and the upper end of the spiral tube is fitted with an insulation sleeve.

[0011] As a further embodiment of the present invention: a temperature-regulating water pipe is placed inside the three-necked bottle. The temperature-regulating water pipe is arranged in a spiral shape. A memory steel wire is installed inside the temperature-regulating water pipe. The upper and lower ends of the temperature-regulating water pipe pass out from the same side of the three-necked bottle. The temperature-regulating water pipe is connected to a temperature-regulating water tank.

[0012] As a further embodiment of the present invention: the aqueous phase receiving box and the organic phase receiving box are symmetrically arranged on the mounting plate. The mounting plate is connected to a driving component. The driving component drives the mounting plate to rotate around the center, causing the organic phase receiving box and the aqueous phase receiving box to successively dock with the bottom of the separating funnel, thereby completing the reception of the organic phase and the aqueous phase.

[0013] As a further embodiment of the present invention: the drive assembly includes a second sliding column, the bottom of which is rotatably mounted between the second sliding column and the operating table, the mounting plate and the second sliding column are slidably mounted together, a drive motor is fixedly mounted at the bottom of the operating table, the drive motor is connected to a drive gear, a rotary gear that meshes with the drive gear is fixedly mounted on the second sliding column, and a lifting cylinder is provided between the rotary gear and the mounting plate.

[0014] As a further embodiment of the present invention: the aqueous phase receiving box is fixedly installed between the receiving box and the mounting plate, the bottom center of the organic phase receiving box is provided with a mounting groove, the mounting plate is provided with a rotary drying motor corresponding to the bottom of the organic phase receiving box, the rotary drying motor is connected with a mating shaft, and the mating shaft and the mounting groove are mutually mated and cooperated.

[0015] As a further embodiment of the present invention: both the aqueous phase receiving box and the organic phase receiving box include a top cover and a receiving tank. The top cover and the receiving tank are threaded together. The top cover is provided with a docking assembly, which includes a receiving hole at the top of the top cover. The receiving hole docks with the bottom of the separating funnel. A matching sliding post is provided at the center of the bottom of the receiving hole. A sealing plate is slidably installed on the matching sliding post. Multiple guide grooves are evenly distributed in a ring on the upper surface of the sealing plate. A supporting spring is provided between the sealing plate and the bottom of the receiving hole. Multiple guide holes are distributed vertically on the side wall of the receiving hole corresponding to the guide grooves. A return groove is provided on the outside of the guide holes. The return groove extends to the bottom of the receiving tank. A return pipe is connected to both ends of the separating funnel and a return pump is provided on the return pipe.

[0016] Compared with the prior art, the beneficial effects of the present invention are: (1) The liquids in the upper and lower layers of the separatory funnel are received by the aqueous phase receiving box and the organic phase receiving box respectively. First, the organic phase receiving box is connected to the bottom of the separatory funnel, and the separatory piston of the separatory funnel is opened to receive the lower organic phase containing sitagliptin. Then, the aqueous phase is connected to the bottom of the separatory funnel to receive the upper aqueous phase.

[0017] (2) The height of the connection point of Adding Tube 2 should be higher than the connection height of Adding Tube 2 to prevent backflow into Adding Tube 2 when adding reagents from Adding Tube 1, and to prevent mixing into the extraction solvent cylinder. At the same time, the speed of adding reagents from Adding Tube 1 should be strictly controlled to prevent excessive flow back into Adding Tube 1. Components such as Adding Tube 1, Adding Tube 2, Extraction Solvent Cylinder and Sealing Cylinder should be made transparent to facilitate real-time observation of reagent addition.

[0018] (3) After the organic phase receiving box completes the receiving of the organic phase containing sitagliptin, it needs to be reintroduced into the separatory funnel for further water washing and layering to improve the purity of the organic phase. After obtaining the purified organic phase, the organic phase receiving box is dried by rotary evaporation. The dichloromethane produced by evaporation is connected to the gas delivery tube, spiral tube and other components through the evaporation tube and combined with the cooling water tank to complete the condensation and liquefaction, thereby recovering it into the extractant cylinder to realize the recovery and reuse of the extractant.

[0019] (4) Adjust the reaction temperature in the three-necked flask by means of a temperature-adjusting water pipe. When adjusting the temperature, stir the liquid in the three-necked flask with a stirring rod to ensure the uniformity of temperature adjustment. The temperature-adjusting water pipe is combined with a memory steel wire to form a spiral shape. After being sent into the three-necked flask through one of its ports, the memory steel wire returns to its original shape and is distributed in a spiral shape on the inner wall edge of the three-necked flask. This facilitates the installation of the suction tube, pH meter, stirring rod and other components in the three-necked flask, and also facilitates the addition of reagents during the reaction process.

[0020] (5) After receiving the organic phase, it needs to be washed and purified with water. A flexible sealing plate is installed on the top of the cover. When the mounting plate is raised, the bottom of the separating funnel is pressed against the sealing plate in the receiving hole until the guide groove on the sealing plate corresponds to the guide hole. At this time, the separating piston of the separating funnel is opened, and the lower organic phase enters the organic phase receiving box through the guide groove, guide hole, and reflux groove. When the organic phase needs to be washed with water, the reflux pipe and reflux pump on the separating funnel are used to pump the organic phase back into the separating funnel using the reflux pipe in the organic phase receiving box. Pure water is added to the separating funnel through the addition pipe for washing, and the separation operation is performed again. The purified organic phase is then received again in the organic phase receiving box to ensure the purity of the subsequent products. Attached Figure Description

[0021] Figure 1 This is a process flow diagram of the present invention.

[0022] Figure 2 This is a schematic diagram of the preparation equipment of the present invention.

[0023] Figure 3 This is a schematic diagram of the internal structure of the device of the present invention.

[0024] Figure 4This is a schematic diagram of the temperature-regulating water pipe in this invention.

[0025] Figure 5 This is a schematic diagram of the internal structure of the enclosed cylinder in this invention.

[0026] Figure 6 This is a schematic diagram of the liquid separation mechanism in this invention.

[0027] Figure 7 This is a schematic diagram of the liquid separator in this invention.

[0028] Figure 8 This is a schematic diagram of the installation of the aqueous phase receiving box and the organic phase receiving box in this invention.

[0029] Figure 9 This is a schematic diagram of the internal structure of the organic phase receiving box in this invention.

[0030] Figure 10 for Figure 9 Enlarged structural diagram at point A in the middle.

[0031] Figure 11 This is a schematic diagram of the driving component in this invention.

[0032] In the diagram: 1. Operating table; 2. Three-necked flask; 20. Temperature-regulating water pipe; 200. Memory steel wire; 21. Support ring; 3. Vacuum filtration pump; 30. Vacuum filtration tube; 4. Sealed cylinder; 5. Cooling water tank; 50. Inlet pipe; 51. Spiral tube; 52. Return pipe; 6. Separating funnel; 601. Reflux pipe; 602. Reflux pump; 60. Extractant cylinder; 61. Fixing frame; 62. Connecting pipe one; 63. Connecting pipe two; 64. Adding pipe one; 65. Adding pipe two; 66. Branch pipe; 67. Control column; 670. Piston; 68. Control motor; 69. Connecting joint; 610. Telescopic... 611. Air pipe; 612. Air pump; 7. Aqueous phase receiving box; 8. Organic phase receiving box; 80. Top cover; 81. Receiving tank; 82. Evaporation tube; 83. Connecting assembly; 830. Receiving hole; 831. Flow guide hole; 832. Sealing plate; 833. Matching slide column one; 834. Support spring; 835. Flow guide groove; 84. Return groove; 85. Mounting groove; 86. Matching shaft; 87. Rotary dryer motor; 9. Drive assembly; 90. Mounting plate; 91. Matching slide column two; 92. Indexing gear; 93. Lifting cylinder; 94. Drive motor; 95. Drive gear. Detailed Implementation

[0033] The technical solution of the present invention will be further described in detail below with reference to specific embodiments.

[0034] Unless otherwise specified, all parts mentioned in this article are by weight. For example, 75 parts of water means 75 parts by weight of water.

[0035] like Figure 1 , Figure 2 , Figure 3 As shown, a method for preparing sitagliptin includes the following steps: S1, adding 75 parts water and 16 parts hydrochloric acid to three-necked flask 2, and cooling to 0℃; S2, adjusting the pH of the three-necked flask to 7.5 by adding isopropylamine dropwise, adding 42.5 parts triethanolamine solution (40 parts water + 2.5 parts triethanolamine), adding 0.2 parts pyridoxal phosphate, and 57 parts DMSO, and controlling the temperature below 10℃; S3, adjusting the pH of the three-necked flask to 8.5 by adding isopropylamine dropwise, and adding 40 parts liquid transaminase (purchased from: Yikelai Biotechnology (Shanghai) Co., Ltd.) S4. When the temperature reaches 45℃, add 20 parts of diketone ((2Z)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7-(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-one), control the temperature at 45℃, add isopropylamine to adjust the pH to 8.5, and keep warm for 24 hours; S5. Filter and extract, cool and crystallize through methyl tert-butyl ether to obtain a white solid, and dry to obtain the finished product sitagliptin.

[0036] like Figure 2 , Figure 3 , Figure 5 As shown, a three-necked flask 2 is placed on an operating table 1. A closed cylinder 4 is installed on the operating table 1. The closed cylinder 4 is connected to a vacuum pump 3. The vacuum pump 3 is connected to a vacuum tube 30, which extends to the bottom of the three-necked flask 2. A liquid separation mechanism is installed inside the closed cylinder 4. The liquid separation mechanism includes a liquid separation funnel 6 and an extractant cylinder 60. An organic phase receiving box 8 and an aqueous phase receiving box 7 are installed on the operating table 1 at the bottom of the closed cylinder 4. The organic phase receiving box 8 and the aqueous phase receiving box 7 are connected to a drive assembly 9. The organic phase receiving box 8 and the aqueous phase receiving box 7 are respectively connected to the liquid separation funnel 6 through the drive assembly 9 to complete the reception of the organic phase and aqueous phase after liquid separation by the liquid separation mechanism. A cooling water tank 5 is also included. The organic phase receiving box 8 is connected to the extractant cylinder 60. The cooling water tank 5 lowers the temperature of the connecting channel between the organic phase receiving box 8 and the extractant cylinder 60, condenses and liquefies the extractant vapor generated by heating and drying the organic phase, and recovers it into the extractant cylinder 60.

[0037] Specifically, prepare a three-necked flask 2 and place it on the support ring 21 of the operating table 1. Add the reagent to the three-necked flask 2 according to the steps of the preparation method described above. After the reaction is complete, use the suction pump 3 and the suction tube 30 to transfer the reaction product in the three-necked flask 2 to the liquid separation mechanism inside the sealed cylinder 4 for extraction and separation. The sealed cylinder 4 forms a closed environment to isolate the extractant that volatilizes during the extraction process and prevent the extractant from escaping to the outside of the sealed cylinder 4.

[0038] More specifically, after extraction, the upper and lower liquid layers of the separatory funnel 6 are received through the aqueous phase receiving tank 7 and the organic phase receiving tank 8, respectively. First, the organic phase receiving tank 8 is connected to the bottom of the separatory funnel 6, and the separatory piston 670 of the separatory funnel 6 is opened to receive the lower organic phase containing sitagliptin. Then, the aqueous phase is connected to the bottom of the separatory funnel 6 through the aqueous phase receiving tank 7 to receive the upper aqueous phase of the separatory funnel 6.

[0039] Furthermore, such as Figure 5 , Figure 6 As shown, the liquid separation mechanism also includes a connecting pipe 62 connected to the top stopper of the liquid separation funnel 6 and a connecting pipe 63. The connecting pipe 62 is connected to the vacuum pump 3. A fixing frame 61 is provided between the extractant cylinder 60 and the liquid separation funnel 6. The fixing frame 61 is fixedly connected to the side wall of the closed cylinder 4. A piston 670 is provided inside the extractant cylinder 60. The piston 670 is connected to a control column 67. The top of the extractant cylinder 60 is connected to an addition pipe 65. The control column 67 passes through the top of the addition pipe 65 and is inserted between the addition pipe 65 and the addition pipe 65. A branch pipe 66 is provided at the top edge of the addition pipe 65. An addition pipe 64 is also provided at the top of the closed cylinder 4. The addition pipe 64 and the addition pipe 65 are respectively connected to the connecting pipe 63.

[0040] Specifically, the vacuum pump 3, combined with the vacuum tube 30 and the connecting tube 62, transfers the reaction product in the three-necked flask 2 to the separatory funnel 6. The control column 67 moves the piston 670 inside the extractant cylinder 60 upwards, injecting the dichloromethane in the extractant cylinder 60 into the connecting tube 63 through the addition tube 65 to perform the extraction operation.

[0041] Furthermore, such as Figure 6 As shown, the height of the connection between the second added tube 65 and the second connected tube 63 is higher than the height of the connection between the first added tube 64 and the second connected tube 63.

[0042] Specifically, the height of the connection point of Addition Tube 2 65 is higher than the connection height of Addition Tube 2 65 itself. This prevents backflow into Addition Tube 2 65 when adding reagents from Addition Tube 1 64, thus preventing contamination into the Extraction Tank 60. Simultaneously, the rate of reagent addition from Addition Tube 1 64 must be strictly controlled to prevent excessive flow and backflow into Addition Tube 1 64. All components, including Addition Tube 1 64, Addition Tube 2 65, Extraction Tank 60, and the Sealing Tank 4, should be made transparent to facilitate real-time observation of reagent addition.

[0043] Furthermore, such as Figure 5 , Figure 9As shown, an evaporator tube 82 is installed on the side wall of the organic phase receiving box 8. A control motor 68 is installed on the side wall of the sealed cylinder 4 at the position corresponding to the evaporator tube 82. The control motor 68 is connected to a connector 69, which is set at a right angle. One end of the connector 69 is mated with the evaporator tube 82, and the other end of the connector 69 is connected to a telescopic tube 610. A gas guide tube 611 is fixedly installed on the inner wall of the sealed cylinder 4. An air pump 612 is installed on the gas guide tube 611. The gas guide tube 611 extends to the upper side of the sealed cylinder 4. A spiral tube 51 is installed on the upper side of the sealed cylinder 4. The gas guide tube 611 is arranged along the inside of the spiral tube 51 and communicates with the lower end of the second adding tube 65. The spiral tube 51 is connected to a cooling water tank 5.

[0044] Specifically, after the organic phase receiving box 8 receives the organic phase containing sitagliptin, it needs to be reintroduced into the separatory funnel 6 for further water washing and layering to improve the purity of the organic phase. After obtaining the purified organic phase, the organic phase receiving box 8 is then subjected to rotary evaporation. The dichloromethane produced by evaporation is connected to components such as the gas guide pipe 611 and the spiral tube 51 through the evaporation tube 82, and condensed and liquefied in conjunction with the cooling water tank 5, thereby recovering it into the extractant cylinder 60 to achieve the recovery and reuse of the extractant.

[0045] More specifically, after rotary drying, the organic phase receiving box 8 is taken out from the closed cylinder 4, methyl tert-butyl ether is added to the organic phase receiving box 8, the organic phase adding box is cooled to 5-10 degrees Celsius and crystallization begins, after filtration, a white solid is obtained, and after drying, the sitagliptin base product is obtained.

[0046] Furthermore, such as Figure 6 As shown, the upper end of the spiral tube 51 passes through the closed cylinder 4 and is connected to the water inlet pipe 50, and the lower end of the spiral tube 51 passes through the closed cylinder 4 and is connected to the water return pipe 52. The water inlet pipe 50 and the water return pipe 52 are respectively connected to the cooling water tank 5. The part of the air guide pipe 611 between the telescopic pipe 610 and the upper end of the spiral tube 51 is fitted with an insulation sleeve.

[0047] Specifically, when the gas-conducting pipe 611 transfers dichloromethane evaporated into a gaseous state, it needs to be kept warm to prevent the dichloromethane from liquefying and flowing back into the organic phase receiving box 8. The water inlet pipe 50 is connected to the upper end of the spiral tube 51 to continuously cool and condense the gas-conducting pipe 611 inside the spiral tube 51, thereby improving the condensation and liquefaction effect.

[0048] Furthermore, such as Figure 3 , Figure 4 As shown, a temperature-regulating water pipe 20 is placed inside the three-necked bottle 2. The temperature-regulating water pipe 20 is arranged in a spiral shape. A memory steel wire 200 is installed inside the temperature-regulating water pipe 20. The upper and lower ends of the temperature-regulating water pipe 20 pass out from the same side of the three-necked bottle 2. The temperature-regulating water pipe 20 is connected to a temperature-regulating water tank.

[0049] Specifically, the reaction temperature inside the three-necked flask 2 is adjusted by the temperature-regulating water pipe 20. When adjusting the temperature, the liquid inside the three-necked flask 2 is stirred by the stirring rod to ensure the uniformity of temperature adjustment. The temperature-regulating water pipe 20 is combined with the memory steel wire 200 to form a spiral shape. After being sent into the three-necked flask 2 through one of its ports, the memory steel wire 200 returns to its original shape and is distributed in a spiral shape along the inner wall edge of the three-necked flask 2. This facilitates the installation of components such as the suction filter tube 30, pH meter, and stirring rod inside the three-necked flask 2, and also facilitates the addition of reagents during the reaction process.

[0050] Furthermore, such as Figure 8 , Figure 11 As shown, the aqueous phase receiving box 7 and the organic phase receiving box 8 are symmetrically arranged on the mounting plate 90. The mounting plate 90 is connected to the driving component 9. The driving component 9 drives the mounting plate 90 to rotate around the center, causing the organic phase receiving box 8 and the aqueous phase receiving box 7 to connect with the bottom of the separating funnel 6 in sequence, thus completing the reception of the organic phase and the aqueous phase.

[0051] Furthermore, such as Figure 8 , Figure 11 As shown, the drive assembly 9 includes a second sliding column 91, the bottom of which is rotatably mounted between the second sliding column 91 and the operating table 1. The mounting plate 90 is slidably mounted between the second sliding column 91 and the operating table 1. A drive motor 94 is fixedly mounted on the bottom of the operating table 1. The drive motor 94 is connected to a drive gear 95. A rotary gear 92 that meshes with the drive gear 95 is fixedly mounted on the second sliding column 91. A lifting cylinder 93 is provided between the rotary gear 92 and the mounting plate 90.

[0052] Specifically, the mounting plate 90 is rotated by the drive motor 94 and the drive gear 95. The rotation angle of the mounting plate 90 is 180 degrees. The organic phase receiving box 8 and the aqueous phase receiving box on the mounting plate 90 are respectively controlled to connect with the bottom of the separating funnel 6. When connecting, the lifting cylinder 93 controls the mounting plate 90 to lift and lower, thereby realizing the receiving of the aqueous phase and organic phase in the separating funnel 6.

[0053] Furthermore, such as Figure 8 , Figure 9 As shown, the aqueous phase receiving box 7 is fixedly installed between the mounting plate 90 and the organic phase receiving box 8. The bottom center position of the organic phase receiving box 8 is provided with a mounting groove 85. The mounting plate 90 is provided with a rotary drying motor 87 corresponding to the bottom of the organic phase receiving box 8. The rotary drying motor 87 is connected to a mating shaft 86. The mating shaft 86 and the mounting groove 85 are mated and cooperate with each other.

[0054] Specifically, after receiving the organic phase, the organic phase receiving box 8 is dried by rotary drying and then methyl tert-butyl ether is added. After cooling and crystallization, the finished product is obtained. The organic phase receiving box 8 is equipped with a heating resistance wire, which, together with the rotary drying motor 87, drives the organic phase receiving box 8 to rotate, thereby evaporating and separating the dichloromethane in the organic phase.

[0055] Furthermore, such as Figure 8 , Figure 9 , Figure 10 As shown, both the aqueous phase receiving tank 7 and the organic phase receiving tank 8 include a top cover 80 and a receiving groove 81. The top cover 80 and the receiving groove 81 are threaded together. The top cover 80 is provided with a docking assembly 83. The docking assembly 83 includes a receiving hole 830 provided at the top of the top cover 80. A matching sliding post 833 is provided at the bottom center of the receiving hole 830. A sealing plate 832 is slidably installed on the matching sliding post 833. Multiple guides are evenly distributed in a ring on the upper surface of the sealing plate 832. A support spring 834 is provided between the bottom of the flow channel 835, the sealing plate 832 and the receiving hole 830. Multiple flow guide holes 831 are distributed on the side wall of the receiving hole 830 in the vertical direction corresponding to the flow guide channel 835. A return channel 84 is provided on the outside of the flow guide hole 831. The return channel 84 extends to the bottom of the receiving tank 81. The liquid separating funnel 6 is connected to the two ends of the liquid separating piston 670 by a return pipe 601. A return pump 602 is provided on the return pipe 601.

[0056] Specifically, after receiving the organic phase, it needs to be washed and purified with water. A flexible sealing plate 832 is installed on the top of the upper cover 80. When the mounting plate 90 is raised, the bottom of the separating funnel 6 is pressed against the sealing plate 832 inside the receiving hole 830 until the guide groove 835 on the sealing plate 832 aligns with the guide hole 831. At this point, the separating piston 670 of the separating funnel 6 is opened, and the lower organic phase enters the organic phase receiving box 8 through the guide groove 835, guide hole 831, and reflux groove 84. When the organic phase needs to be washed with water, using the reflux pipe 601 and reflux pump 602 on the separating funnel 6, the organic phase is pumped back into the separating funnel 6 using the reflux pipe 601 inside the organic phase receiving box 8. Pure water is added to the separating funnel 6 through the addition pipe 64 for washing, and the separation operation is performed again. The purified organic phase is then received again in the organic phase receiving box 8 to ensure the purity of the subsequent products.

[0057] The working principle of this invention embodiment is as follows: like Figures 1-11As shown, after extraction, the upper and lower liquid layers of the separatory funnel 6 are collected through the aqueous phase receiving tank 7 and the organic phase receiving tank 8, respectively. First, the organic phase receiving tank 8 is connected to the bottom of the separatory funnel 6, and the separatory piston 670 of the separatory funnel 6 is opened to collect the lower organic phase containing sitagliptin. Then, the aqueous phase is connected to the bottom of the separatory funnel 6 through the aqueous phase receiving tank 7 to collect the upper aqueous phase. The height of the connection point of the second addition tube 65 is higher than the connection height of the second addition tube 65 to prevent backflow into the second addition tube 65 when adding reagents from the first addition tube 64, and to prevent mixing into the extraction solvent cylinder 60. At the same time, the speed of adding reagents from the first addition tube 64 needs to be strictly controlled to prevent excessive flow and backflow into the first addition tube 64. The first addition tube 64, the second addition tube 65, the extraction solvent cylinder 60, and the sealing cylinder 4 need to be made transparent to facilitate real-time observation of the reagent addition. After the organic phase receiving box 8 receives the organic phase containing sitagliptin, it needs to be reintroduced into the separating funnel 6 for further water washing and layering to improve the purity of the organic phase. After obtaining the purified organic phase, the organic phase receiving box 8 is then subjected to rotary evaporation. The dichloromethane produced by evaporation is connected to components such as the gas delivery pipe 611 and the spiral tube 51 via the evaporation tube 82, and condensed and liquefied in conjunction with the cooling water tank 5, thus being recovered into the extractant cylinder 60 for reuse. When the gas delivery pipe 611 transfers the evaporated gaseous dichloromethane, it needs to be kept warm to prevent the dichloromethane from liquefying and flowing back into the organic phase receiving box 8. The water inlet pipe 50 is connected to the upper end of the spiral tube 51, continuously cooling and condensing the gas delivery pipe 611 inside the spiral tube 51 to improve the condensation and liquefaction effect. The reaction temperature inside the three-necked flask 2 is adjusted by the temperature-regulating water pipe 20. During temperature adjustment, the liquid inside the three-necked flask 2 is stirred by the stirring rod to ensure uniform temperature regulation. The temperature-regulating water pipe 20 is combined with the memory steel wire 200 to form a spiral shape. After being sent into the three-necked flask 2 through one of its ports, the memory steel wire 200 returns to its original shape and is distributed in a spiral shape along the inner wall edge of the three-necked flask 2. This facilitates the installation of components such as the suction filter tube 30, pH meter, and stirring rod inside the three-necked flask 2, and also facilitates the addition of reagents during the reaction process. After receiving, the organic phase needs to be washed and purified with water. A flexible sealing plate 832 is installed on the top of the cover 80. When the mounting plate 90 is raised, the bottom of the separating funnel 6 is pressed against the sealing plate 832 in the receiving hole 830 until the guide groove 835 on the sealing plate 832 corresponds to the guide hole 831. At this time, the separating piston 670 of the separating funnel 6 is opened, and the lower organic phase enters the organic phase receiving box 8 through the guide groove 835, the guide hole 831, and the reflux groove 84.When the organic phase needs to be washed with water, the organic phase is pumped back into the separating funnel 6 using the reflux pipe 601 and reflux pump 602 on the separating funnel 6 and the reflux pipe 601 in the organic phase receiving box 8. Pure water is then added to the separating funnel 6 through the addition pipe 64 for washing. The separation operation is performed again, and the purified organic phase is re-received in the organic phase receiving box 8 to ensure the purity of the subsequent products.

[0058] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.

[0059] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A process for the preparation of sitagliptin base, characterized by, Comprising the following steps: S1, add water 75 parts, hydrochloric acid 16 parts to the three-port bottle (2), and cool to 0 DEG C; S2, drop isopropylamine to adjust the pH of the three-port bottle (2) to 7.5, add 42.5 parts of triethanolamine solution, 0.2 parts of pyridoxal phosphate, 57 parts of DMSO, and control the temperature below 10 DEG C; S3, drop isopropylamine to adjust the pH of the three-port bottle (2) to 8.5, add 40 parts of liquid transaminase, and slowly warm to 40-45 DEG C; S4, when the temperature rises to 45 DEG C, drop 20 parts of diketone, control the temperature at 45 DEG C, drop isopropylamine to adjust the pH to 8.5, and incubate for 24 hours; S5, extract by suction filtration, cool crystallize white solid with methyl tert-butyl ether, and dry to obtain finished sitagliptin base.

2. The process for the preparation of sitagliptin base as claimed in claim 1 wherein, The three-port bottle (2) is placed on the operation table (1), the operation table (1) is provided with a closed cylinder (4), the closed cylinder (4) is connected with a suction filter pump (3), the suction filter pump (3) is connected with a suction filter pipe (30), the suction filter pipe (30) extends to the bottom of the three-port bottle (2), a liquid separation mechanism is arranged in the closed cylinder (4), the liquid separation mechanism comprises a separation funnel (6) and an extractant cylinder (60), the operation table (1) at the bottom of the closed cylinder (4) is provided with an organic phase receiving tank (8) and an aqueous phase receiving tank (7), the organic phase receiving tank (8) and the aqueous phase receiving tank (7) are connected with a driving assembly (9), the organic phase receiving tank (8) and the aqueous phase receiving tank (7) are respectively connected with the separation funnel (6) through the driving assembly (9), the organic phase and the aqueous phase after being separated by the liquid separation mechanism are received, and the application further comprises a refrigerated water tank (5) connected between the organic phase receiving tank (8) and the extractant cylinder (60), the refrigerated water tank (5) reduces the temperature of a connecting channel between the organic phase receiving tank (8) and the extractant cylinder (60), condenses and liquefies the extractant vapor generated by heating and drying the organic phase, and recycles the extractant vapor into the extractant cylinder (60).

3. The process for the preparation of sitagliptin base as claimed in claim 2, wherein, The liquid separation mechanism further comprises a first connecting pipe (62) connected with a bottle plug at the top of the separation funnel (6) and a second connecting pipe (63), the first connecting pipe (62) is connected with the suction filter pump (3), a fixing frame (61) is arranged between the extractant cylinder (60) and the separation funnel (6), the fixing frame (61) is fixedly connected between the extractant cylinder (60) and the side wall of the closed cylinder (4), a piston (670) is arranged in the extractant cylinder (60), the piston (670) is connected with a control column (67), the top of the extractant cylinder (60) is connected with a second adding pipe (65), the control column (67) passes through the top of the second adding pipe (65) and is inserted between the second adding pipe (65), an edge of the top of the second adding pipe (65) is provided with a branch pipe (66), the top of the closed cylinder (4) is further provided with a first adding pipe (64), and the first adding pipe (64) and the second adding pipe (65) are respectively connected with the second connecting pipe (63).

4. The process for the preparation of sitagliptin base as claimed in claim 3 wherein, The height of the connecting position between the second adding pipe (65) and the second connecting pipe (63) is higher than the height of the connecting position between the first adding pipe (64) and the second connecting pipe (63).

5. The process for the preparation of sitagliptin base as claimed in claim 2, wherein, The side wall of the organic phase receiving tank (8) is provided with an evaporation pipe (82), the side wall of the closed cylinder (4) is provided with a control motor (68) corresponding to the position of the evaporation pipe (82), the control motor (68) is connected with a butt joint (69), the butt joint (69) is arranged at right angles, one end of the butt joint (69) and the evaporation pipe (82) are matched with each other, the other end of the butt joint (69) is connected with an extension pipe (610), the inner wall of the closed cylinder (4) is fixedly installed with a gas guide pipe (611), the gas guide pipe (611) is provided with a gas pump (612), the gas guide pipe (611) extends to the upper side of the closed cylinder (4), the upper side of the closed cylinder (4) is provided with a spiral pipe (51), the gas guide pipe (611) is arranged inside the spiral pipe (51) and communicates with the lower end of the adding pipe two (65), and the spiral pipe (51) is connected with a refrigerated water tank (5).

6. The process for the preparation of sitagliptin base as claimed in claim 5 wherein, The upper end of the spiral pipe (51) penetrates out of the closed cylinder (4) and is connected with a water inlet pipe (50), the lower end of the spiral pipe (51) penetrates out of the closed cylinder (4) and is connected with a water return pipe (52), and the water inlet pipe (50) and the water return pipe (52) are connected with the refrigerated water tank (5) respectively, and the part of the gas guide pipe (611) between the extension pipe (610) and the upper end of the spiral pipe (51) is sleeved with a heat preservation sleeve.

7. The process for the preparation of sitagliptin base as claimed in claim 2, wherein, The three-necked bottle (2) is placed with a temperature regulating water pipe (20), the temperature regulating water pipe (20) is arranged in a spiral shape, the memory steel wire (200) is installed in the temperature regulating water pipe (20), and the upper and lower ends of the temperature regulating water pipe (20) penetrate out of the same side pipe opening part of the three-necked bottle (2), and the temperature regulating water pipe (20) is connected with a temperature regulating water tank.

8. The process for the preparation of sitagliptin base as claimed in claim 2, wherein, The water phase receiving tank (7) and the organic phase receiving tank (8) are symmetrically arranged on the mounting plate (90), the mounting plate (90) is connected with a driving assembly (9), the driving assembly (9) drives the mounting plate (90) to rotate around the center to drive the organic phase receiving tank (8) and the water phase receiving tank (7) to be matched with the bottom of the separatory funnel (6) in turn, and the receiving of the organic phase and the water phase is completed.

9. The process for the preparation of sitagliptin base as claimed in claim 8, wherein, The driving assembly (9) comprises a matching slide column two (91), the bottom of the matching slide column two (91) is rotatably installed between the operation table (1), the mounting plate (90) is slidably and matchingly installed between the matching slide column two (91), the bottom of the operation table (1) is fixedly provided with a driving motor (94), the driving motor (94) is connected with a driving gear (95), the matching slide column two (91) is fixedly provided with a shift gear (92) which is matched with the driving gear (95), and the shift gear (92) and the mounting plate (90) are provided with a lifting cylinder (93).

10. The process for the preparation of sitagliptin base as claimed in claim 8, wherein, The water phase receiving tank (7) is fixedly installed between the mounting plate (90), a mounting groove (85) is arranged at the bottom center position of the organic phase receiving tank (8), the mounting plate (90) is provided with a spin-drying motor (87) corresponding to the bottom of the organic phase receiving tank (8), the spin-drying motor (87) is connected with a matching shaft (86), and the matching shaft (86) and the mounting groove (85) are mutually connected and matched; The water phase receiving tank (7) and the organic phase receiving tank (8) all comprise an upper cover (80) and a containing groove (81), the upper cover (80) and the containing groove (81) are threadedly connected, the upper cover (80) is provided with a butt joint assembly (83), the butt joint assembly (83) comprises a receiving hole (830) arranged at the top of the upper cover (80), the receiving hole (830) and the bottom of the separating funnel (6) are mutually connected, a matching slide column I (833) is arranged at the bottom center position of the receiving hole (830), a blocking disc (832) is slidably installed on the matching slide column I (833), a plurality of flow guide grooves (835) are uniformly distributed on the upper surface of the blocking disc (832), a supporting spring (834) is arranged between the blocking disc (832) and the bottom of the receiving hole (830), a plurality of flow guide holes (831) are arranged in the vertical direction of the flow guide grooves (835) on the sidewall of the receiving hole (830), a backflow groove (84) is arranged outside the flow guide hole (831), the backflow groove (84) extends to the bottom of the containing groove (81), the separating funnel (6) is provided with a backflow pipe (601) communicated at both ends of the separating piston (670), and the backflow pipe (601) is provided with a backflow pump (602).

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