Process for the synthesis of N-acetyl-DL-leucine green acylate with high selectivity

Abstract

This invention relates to the field of green synthesis technology of amino acid derivatives, and discloses a highly selective green acylation synthesis process for N-acetyl-DL-leucine. The process includes: pre-drying the DL-leucine raw material; constructing an acylation reaction system under weakly alkaline conditions using water as the main solvent; slowly adding acetic anhydride after cooling while maintaining the system at a weakly alkaline state; and performing the reaction at a sustained temperature followed by impurity removal, acidification crystallization, solid-liquid separation, washing, recrystallization, and drying to obtain the N-acetyl-DL-leucine product. This process can be implemented in a reactor equipped with petal-shaped guide rails, a transmission mechanism, and an annular corrugated plate to enhance mixing and heat and mass transfer, thereby improving acylation selectivity, product purity, batch stability, and reducing the amount of organic solvent used.

Description

Technical Field

[0001] This invention relates to the field of green synthesis technology of amino acid derivatives, and in particular to a highly selective green acylation synthesis process for N-acetyl-DL-leucine. Background Technology

[0002] N-acetyl-DL-leucine is an important class of amino acid derivatives with high application value in pharmaceutical intermediates, functional material precursors, and fine chemicals. In existing technologies, the preparation of these compounds typically involves the selective acylation of leucine substrates with acylating agents to obtain the corresponding N-acetylated products. With the continuous advancement of green manufacturing concepts, using water as the main solvent, reducing the amount of high-boiling-point organic solvents used, and simultaneously achieving high reaction selectivity and high product purity have become important development trends in this technology. However, amino acid substrates themselves exhibit amphoteric characteristics; their ionization state, dissolution and dispersion behavior in aqueous environments, and sensitivity to local pH changes are strong. This makes the acylation process not only dependent on the chemical formulation itself but also highly dependent on the mixing capacity, heat transfer capacity, and micro-diffusion efficiency of the reaction equipment during the dropping stage.

[0003] The existing reaction vessels used for the synthesis of N-acetyl-DL-leucine still have several shortcomings in industrial practice: Firstly, conventional reactors often employ a single rotating stirring path with a fixed radius, which can easily lead to uneven distribution of concentration and temperature fields in the near-wall region, bottom region, and local feeding region. This results in localized high-concentration hydrolysis of acetic anhydride after it enters the system, reducing the effective acylation utilization rate. Secondly, for weakly basic acylation systems with water as the main solvent, local pH shifts directly affect the effective nucleophilic state of the amino group, thus significantly impacting the N-position acylation selectivity. Third, if the initial impurity removal is insufficient or the stirring flow field is monotonous during the subsequent acid precipitation and crude product formation process, it is easy to induce problems such as uncontrolled crystal nucleus formation, excessively wide particle size distribution, and increased mother liquor entrainment, which in turn affect the filterability and recrystallization burden of the crude product. Summary of the Invention

[0004] The purpose of this invention is to provide a highly selective green acylation synthesis process for N-acetyl-DL-leucine, which solves the problems of uneven mixing, local hydrolysis, increased side reactions, unstable crystal quality, and insufficient scale-up reproducibility in the prior art.

[0005] To achieve the above objectives, the present invention adopts the following technical solution: A highly selective green acylation synthesis process for N-acetyl-DL-leucine includes the following steps: Step 1: Pre-drying the DL-leucine raw material to reduce fluctuations in its water content, obtaining pre-treated DL-leucine; Step 2: Adding the pre-treated DL-leucine to a reaction vessel, using water as the main solvent, and adding an alkaline regulator under stirring to adjust the reaction system to a weakly alkaline state, obtaining an acylation reaction system; Step 3: Cooling the acylation reaction system obtained in Step 2, and slowly adding acetic anhydride to the acylation reaction system under stirring to carry out the acylation reaction, maintaining a constant temperature during the addition of acetic anhydride. The acylation reaction system is weakly alkaline; Step 4: After the acetic anhydride is added, continue the reaction at a constant temperature to fully convert DL-leucine and obtain the acylation reaction solution; Step 5: Remove impurities from the acylation reaction solution to obtain a clear solution; Step 6: Acidify the clear solution to precipitate N-acetyl-DL-leucine and obtain a crude slurry; Step 7: Perform solid-liquid separation and washing on the crude slurry to obtain crude N-acetyl-DL-leucine; Step 8: Recrystallize and purify the crude N-acetyl-DL-leucine; Step 9: Dry the recrystallized wet crystals to obtain the finished N-acetyl-DL-leucine product.

[0006] Preferably, in step one, the temperature of the pre-drying treatment is 40-80℃, and the moisture content of DL-leucine after pre-drying is not higher than 1.0wt%; in step two, the alkalinity regulator is one or more of sodium carbonate, sodium bicarbonate, and sodium hydroxide, and the pH of the acylation reaction system is controlled to be 7.5-9.5; in step two, ethanol may also be added as a co-solvent, and the volume fraction of ethanol is not higher than 20% of the total volume of the reaction system.

[0007] Preferably, in step three, the acylation reaction temperature is 0–15°C, the molar ratio of DL-leucine to acetic anhydride is 1:1.00–1.20, the acetic anhydride is added over a period of 0.5–2 h, and the pH of the reaction system is controlled at 7.5–9.5 during the addition process; in step four, the heat preservation reaction time is 0.5–3 h, and the heat preservation reaction temperature is 5–25°C.

[0008] Preferably, in step six, the acidification treatment uses one of hydrochloric acid, acetic acid, or citric acid to adjust the pH of the system to 1.5–3.0, and crystallizes at 0–10°C; in step eight, the recrystallization purification uses water or a water-ethanol mixed solvent.

[0009] Preferably, the reaction vessel used in step two includes: a vessel body with a lid installed on its top, and a motor installed above the lid; a stirring mechanism located inside the vessel body for stirring the materials inside the vessel body; a petal-shaped guide rail installed on the bottom surface of the lid and slidably connected to the stirring mechanism; a transmission mechanism connected to the motor and the stirring mechanism for driving the stirring mechanism to rotate when the motor is running and driving the stirring mechanism to move along the petal-shaped guide rail; and an annular wave plate installed on the inner bottom surface of the vessel body and in contact with the bottom of the stirring mechanism.

[0010] Preferably, the reactor further includes: multiple temperature control plates, all embedded in the side wall of the reactor body; a first feeding pipe, which is installed through the side wall of the reactor body; a second feeding pipe, which is installed through the side wall of the reactor body; and a discharge pipe, which is installed through the bottom surface of the reactor body.

[0011] Preferably, the stirring mechanism includes: a vertical rod with a slider and a prism fixedly connected to its upper and lower ends respectively, the slider being slidably connected to a guide groove on a petal-shaped guide rail; a cylinder with a slot matching the prism inside, the prism being slidably connected to the cylinder; multiple stirring rods, all mounted on the outer circumferential surface of the cylinder; ball bearings, mounted on the bottom surface of the cylinder, rolling in contact with the upper surface of the annular wave plate; and a third gear, fixedly sleeved on the vertical rod.

[0012] Preferably, the transmission mechanism includes: a shaft that passes through the vessel lid and is rotatably connected to the vessel lid, with its upper end fixedly connected to the power output shaft of the motor; a first gear that is fixedly sleeved on the shaft; a rotating shaft on which a second gear is fixedly sleeved, the second gear meshing with the first gear and the third gear; a first hinge plate with its two ends hinged to the shaft and the rotating shaft respectively; and a second hinge plate with its two ends hinged to the rotating shaft and the vertical rod respectively.

[0013] Preferably, the transmission mechanism further includes: a drive plate, fixedly connected to the shaft; a strip groove, which is formed through the drive plate, and the vertical rod passes through the strip groove and is slidably connected to the strip groove.

[0014] Preferably, the reactor further includes: multiple support legs, all installed on the bottom surface of the reactor body; a fixing frame, installed on the top surface of the reactor cover, and the motor is installed on the fixing frame; and a heat insulation seat, installed on the outer surface of the reactor body, on which a controller is installed.

[0015] In summary, due to the adoption of the above technical solution, the beneficial effects of the present invention are: 1. In this invention, by pre-drying the DL-leucine raw material before it enters the reaction system, the influence of the raw material moisture content fluctuation on the subsequent reaction can be reduced, making the initial state of each batch of raw material more stable when it enters the system, which is beneficial to controlling batch-to-batch consistency.

[0016] 2. In this invention, by setting up a complete post-processing flow including impurity removal, acidification crystallization, solid-liquid separation, washing, recrystallization and drying, reaction impurities can be removed upstream, and the crystal purity and quality can be improved through controlled acid precipitation and recrystallization. Then, a stable finished product can be obtained through drying. Therefore, overall, it is beneficial to obtain N-acetyl-DL-leucine products with high purity, stable quality and easy industrial scale-up.

[0017] 3. The reactor in this invention, by setting up a reactor body, supporting legs, reactor lid, fixing frame, motor, stirring mechanism, petal-shaped guide rail, guide groove, transmission mechanism and annular wave plate, can realize the combined stirring of revolution, rotation, radial reciprocating and vertical undulation under the drive of a single motor. This enhances the macroscopic circulation inside the reactor, the renewal of the near-wall boundary layer and the suspension of bottom particles, improves the heat and mass transfer conditions, reduces the accumulation of material in dead corners, and provides a uniform reaction environment for highly selective acylation. Attached Figure Description

[0018] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0019] Figure 1 This is a flowchart illustrating the highly selective N-acetyl-DL-leucine green acylation synthesis process of this invention. Figure 2 This is a perspective view of the reaction vessel in this invention; Figure 3 This is a schematic diagram of the interior of the vessel body in this invention; Figure 4 This is a schematic diagram of the assembly structure of the stirring mechanism, petal-shaped guide rail, transmission mechanism and annular wave plate in this invention; Figure 5 This is a schematic diagram of the assembly structure of the stirring mechanism, transmission mechanism and annular wave plate in this invention; Figure 6 In this invention Figure 5 Enlarged schematic diagram of part A; Figure 7 In this invention Figure 5 Exploded view; Figure 8This is a schematic diagram of the assembly structure of the stirring mechanism and the transmission mechanism in this invention; Reference numerals: 100, Reactor; 101, Reactor body; 102, First feed pipe; 103, Second feed pipe; 104, Discharge pipe; 105, Support leg; 106, Reactor lid; 107, Fixing frame; 108, Motor; 110, Stirring mechanism; 111, Vertical rod; 112, Prism; 113, Insert; 114, Stirring rod; 115, Ball bearing; 116, Sliding block; 117, Third gear; 121, Petal-shaped guide rail; 122, Guide groove; 130, Transmission mechanism; 131, Shaft; 132, First gear; 133, Rotating shaft; 134, Second gear; 135, First hinge plate; 136, Second hinge plate; 137, Drive plate; 138, Strip groove; 140, Annular wave plate; 151, Heat insulation seat; 152, Controller. Detailed Implementation

[0020] To make the above-mentioned objects, features, and advantages of the present invention more apparent and understandable, specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the protection scope of the present invention.

[0021] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0022] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0023] This invention is described in detail with reference to the accompanying drawings. When detailing the embodiments of this invention, for ease of explanation, the cross-sectional views illustrating the device structure may be partially enlarged, not to scale. Furthermore, the accompanying drawings are merely examples and should not be construed as limiting the scope of protection of this invention. In actual fabrication, the three-dimensional spatial dimensions of length, width, and depth should be included.

[0024] Furthermore, it should be noted in the description of this invention that the terms "first," "second," or "third" are used for descriptive purposes only and should not be construed as indicating or implying relative importance.

[0025] Unless otherwise explicitly specified and limited, the terms "installation," "connection," and "joining" in this invention should be interpreted broadly. For example, they can refer to fixed connections, detachable connections, or integral connections; similarly, they can refer to mechanical connections, electrical connections, or direct connections, or indirect connections through an intermediate medium, or internal connections between two components. Those skilled in the art can understand the specific meaning of the above terms in this invention based on the specific circumstances.

[0026] Example 1: A highly selective green acylation synthesis process for N-acetyl-DL-leucine, comprising the following steps: Step 1: Pre-dry the DL-leucine raw material to reduce fluctuations in the moisture content of the raw material and obtain pre-treated DL-leucine; Step 2: The pretreated DL-leucine is added into the reaction vessel 100 through the first feeding pipe 102. Water is then added into the vessel body 101 as the main solvent. Under the condition that the stirring mechanism 110 is driven by the motor 108, an alkaline regulator is added into the system through the second feeding pipe 103 to keep the reaction system in a weakly alkaline state and form an acylation reaction system. Step 3: After the acylation reaction system is formed in step 2, the temperature is controlled by multiple temperature control plates set on the side wall of the reactor body 101. Then, acetic anhydride is slowly added through the second feed pipe 103. After entering the liquid phase, the acetic anhydride reacts with the leucine substrate dispersed or dissolved in the form of salt. During the dropwise addition, the system is continuously controlled to maintain a weakly alkaline state so that the consumption of acetic anhydride and the neutralization of by-product acid are carried out simultaneously to suppress local acidification. Step 4: After the acetic anhydride has been added, continue stirring and keeping the reaction at a constant temperature to ensure that DL-leucine is fully converted and to obtain the acylation reaction solution; Step 5: Remove impurities from the acylation reaction solution obtained in Step 4 to obtain a clear solution. Impurity removal can be achieved by activated carbon adsorption followed by filtration, or by heat-insulated filtration to remove insoluble matter, trace colloidal impurities, and pigment impurities.

[0027] Step Six: Acidify the clarified liquid to precipitate N-acetyl-DL-leucine, obtaining crude slurry. During acidification, the acid solution should be added slowly while stirring simultaneously. Step 7: Perform solid-liquid separation and washing on the crude slurry to obtain crude N-acetyl-DL-leucine. The washing solution is preferably low-temperature purified water. Step 8: Recrystallize and purify the crude N-acetyl-DL-leucine. After heating to dissolve, keeping warm to clarify, slowly cooling and keeping warm at low temperature, the crude product forms crystals with higher purity.

[0028] Step 9: The recrystallized wet crystals were dried at 55°C under vacuum for 6 hours to obtain a white N-acetyl-DL-leucine product.

[0029] The test results showed that the product had an HPLC purity of 99.1 wt%, a separation yield of 86.8 wt%, and a moisture content of 0.30 wt% after drying.

[0030] In this embodiment, the pre-drying temperature in step one is 60°C, the pre-drying time is 4 hours, and the moisture content of DL-leucine after pre-drying is 0.4 wt%.

[0031] In this embodiment, the alkalinity regulator in step two is preferably one or more of sodium carbonate, sodium bicarbonate, and sodium hydroxide. Sodium carbonate and sodium bicarbonate both act as neutralizing buffers, absorbing byproduct acids relatively smoothly during the dynamic process of adding acetic anhydride, thus reducing localized strong acidification or alkalization. Sodium hydroxide has higher alkalinity and can be used for rapid pH correction, but it is preferred to use it in combination with carbonates to avoid increased side reactions caused by localized strong alkali. The pH of the system is controlled between 8.2 and 8.8 to balance the effective activity of the amino group and the stability of the acetic anhydride. If the pH is below this range, the nucleophilic attack ability decreases, and the target acylation rate decreases. If it is above this range, it may exacerbate side reactions and the formation of certain impurities.

[0032] In step two, ethanol can be added as a co-solvent, but the volume fraction of ethanol should not exceed 20% of the total volume of the reaction system. By adding a small amount of ethanol as a co-solvent, local wettability and phase distribution can be adjusted, and mass transfer conditions in certain stages can be improved. However, the proportion of ethanol should not be too high, otherwise it will weaken the green properties of water as the main solvent and may change the subsequent acid precipitation and crystallization behavior. The above parameter combination makes the process controllable, repeatable, and environmentally friendly.

[0033] In this embodiment, the acylation reaction temperature in step three is 5°C, the preferred molar ratio of DL-leucine to acetic anhydride is 1:1.08, the acetic anhydride dropping time is 1 hour, and the pH of the reaction system is controlled between 8.2 and 8.8 during the dropping process. As an acylation agent, the utilization efficiency of acetic anhydride in the aqueous phase is highly dependent on temperature and the feeding rhythm. The dropping time determines the instantaneous local concentration distribution in the reaction system. If the dropping is too fast, a high concentration zone of acetic anhydride will form near the second feed pipe 103, which is prone to non-target consumption before homogeneous dispersion is completed. If the dropping is too slow, the overall reaction cycle will be prolonged, increasing equipment occupancy. Setting the dropping time between 0.5 hours and 2 hours achieves a balance between engineering feasibility and selectivity.

[0034] In this embodiment, the preferred heat preservation reaction time in step four is 1.5 hours, and the heat preservation reaction temperature is 15°C. The heat preservation stage in step four is not simply an extension of time, but rather takes advantage of the fact that the system components are already relatively uniformly dispersed after the droplet addition, so that the tail-end reaction is carried out under a small concentration difference, thereby reducing the residue of unreacted substrate.

[0035] In this embodiment, the acidification treatment in step six can be performed using hydrochloric acid, acetic acid, or citric acid to adjust the pH of the system to 2.2, followed by crystallization at 3°C. Hydrochloric acid is a strong inorganic acid with a fast acidification rate, suitable for use when a rapid acidic environment needs to be established. Acetic acid is a weak organic acid with a milder acidification rate, suitable for controlling the rate of crystal nucleus formation. Citric acid has the characteristics of both polybasic acids and exhibits a milder release characteristic to localized acidity changes. Low-temperature crystallization helps reduce the solubility of the product, increases the precipitation rate, and promotes crystal growth along more stable crystal planes. If the acidification and cooling are too drastic, a large number of fine crystal nuclei may be generated instantaneously, which can easily lead to the formation of aggregated crystals or fine powder that is difficult to filter. Recrystallization using water or a mixture of water and ethanol further utilizes the difference in solubility and solvent selectivity to remove impurities, improving the purity, color, and crystal uniformity of the final product.

[0036] In this embodiment, a mixed solvent of water and ethanol is used for recrystallization purification in step eight.

[0037] Table 1: Experimental results for different process parameter groups

[0038] As shown in Table 1, Example 1 achieved the most balanced performance in terms of purity, yield, and overall color when using a moderate parameter combination. Specifically, step one, by controlling the moisture content of the raw material to a low rather than extreme level, ensured the stability of the raw material while avoiding the risk of agglomeration due to overheating. Steps two and three, by controlling the system within the moderately weakly alkaline range and the medium-low temperature dropping range, ensured the effective reactivity of the amino group while avoiding the aggravated local hydrolysis of acetic anhydride, thus significantly promoting both HPLC purity and yield. Step six, by using a lower crystallization temperature and controlling the pH at approximately 2.2, achieved good coarse crystal filtration and low entrainment. Step nine, by using vacuum drying at 55°C, achieved a good balance between overall color and residual moisture. The overall color was determined by comparison with a standard color chart.

[0039] Control group 1 showed that when the pre-drying in step one was insufficient, the addition in step three was too fast and the temperature was too high, and the driving force for acid precipitation in step six was too weak, although the overall situation was still within the scope of the claims, fluctuations in the moisture content of the raw materials, local reaction peaks and insufficient acid precipitation would occur in combination, resulting in a significant decrease in purity and yield.

[0040] Control group 2 showed that although using a lower acylation temperature and a longer dropping time was beneficial to improve selectivity, excessively high alkalinity, higher acylation agent excess, and excessively long reaction cycle would result in additional energy consumption and process time, and therefore the overall color was not as good as in Example 1.

[0041] Control group 3 showed that when steps three and four were biased towards a high-temperature, short-time window, both selectivity and yield were adversely affected.

[0042] Control group 4 showed that steps six and eight had a significant impact on crystal quality, with milder acidification and recrystallization with single water leading to increased mother liquor entrainment.

[0043] Control group 5 showed that although higher drying temperatures could further reduce residual moisture, they were more likely to cause the finished product to turn slightly yellow. Therefore, step nine should be controlled within a moderate temperature range.

[0044] Example 2: As Figures 2 to 8 As shown, compared with Example 1, the only difference is that the reaction vessel 100 used in step two is mainly composed of a vessel body 101, a support leg 105, a vessel cover 106, a fixing frame 107, a motor 108, a stirring mechanism 110, a petal-shaped guide rail 121, a guide groove 122, a transmission mechanism 130, and an annular wave plate 140.

[0045] A lid 106 is mounted on the top of the vessel body 101, and a motor 108 is mounted above the lid 106. A stirring mechanism 110 is located inside the vessel body 101 and is used to stir the materials inside the vessel body 101. A petal-shaped guide rail 121 is mounted on the bottom surface of the lid 106 and is slidably connected to the stirring mechanism 110. A transmission mechanism 130 is connected to the motor 108 and the stirring mechanism 110. When the motor 108 is running, the transmission mechanism 130 drives the stirring mechanism 110 to rotate and moves it along the petal-shaped guide rail 121. An annular wave plate 140 is mounted on the inner bottom surface of the vessel body 101 and contacts the bottom of the stirring mechanism 110. The petal-shaped guide rail 121 has a circumferential undulating profile. The transmission mechanism 130 is located near the center area of ​​the petal-shaped guide rail 121, and the stirring mechanism 110 moves around the shaft 131 with a variable radius under the constraint of the guide groove 122.

[0046] Specifically, traditional reactors typically employ a single central axis fixed agitator with the impeller rotating around a fixed radius. While this design offers the advantage of simple structure, it also results in a relatively fixed flow field, often leading to flow weakening zones near the sidewalls, bottom corners, and the vicinity of the central axis. For systems involving aqueous acylation and subsequent crystallization, localized concentration and temperature inhomogeneities directly impact selectivity and crystal quality.

[0047] The reactor 100 used in this invention, through a non-circular guiding structure of the petal-shaped guide rail 121, allows the trajectory of the stirring mechanism 110 to no longer be a simple circle, but rather to periodically approach and move away from the shaft 131 following the radial undulation of the guide groove 122. In this way, the stirring rod 114 sweeps across different radii at different times, effectively changing the stirring radius and shear coverage area. Simultaneously, the annular wave plate 140 provides axial undulation support at the bottom, allowing the insert 113 and the stirring rod 114 to gain additional vertical displacement during movement. Therefore, the stirring mechanism 110, under a single power source, can complete a quadruple combined motion of revolution, rotation, radial reciprocating motion, and vertical undulation, enhancing the three-dimensional circulation of the fluid and slurry. This allows for more thorough renewal of the boundary layer and dispersal of local agglomerates. For the liquid-phase acylation process in steps two and three, this quadruple combined motion helps shorten the local diffusion time of acetic anhydride after entering the liquid phase, reduces the peak concentration in micro-areas, and improves selectivity.

[0048] like Figure 2 and Figure 3 As shown, the reaction vessel 100 also includes multiple temperature control plates, a first feed pipe 102, a second feed pipe 103, and a discharge pipe 104. The multiple temperature control plates are embedded in the side wall of the vessel body 101, and are integrated heating and cooling temperature control plates. The first feed pipe 102 is installed through the side wall of the vessel body 101 and is used to add DL-leucine, purified water, or some auxiliary materials. The second feed pipe 103 is installed through the side wall of the vessel body 101 and is used to add acetic anhydride, alkaline solution, or acidification medium. The discharge pipe 104 is installed through the bottom surface of the vessel body 101 and is used to discharge the acylated liquid after the reaction or the slurry from subsequent steps.

[0049] Specifically, the temperature control plate is directly embedded in the side wall of the vessel body 101. Its heat first acts on the near-wall liquid region where the boundary layer is most easily formed, and then the near-wall fluid is continuously brought into the main flow field by the variable trajectory motion of the stirring mechanism 110, which helps to improve heat utilization efficiency and reduce the thickness of the temperature difference layer. Compared with single bottom heating, side-wall distributed heating is more suitable for fine chemical processes that require switching between heating and cooling and maintaining a mild thermal field.

[0050] The first feed pipe 102 and the second feed pipe 103 are set separately, so that the feeding of solid or main solvent can be separated from the feeding of acylating agent, alkali solution, and acid solution, avoiding excessive local contact of sensitive materials at the same inlet. The discharge pipe 104 is located at the bottom, which can quickly discharge the liquid or slurry in the vessel when the stirring is stopped or the operation is at low speed, reducing residue.

[0051] like Figures 3 to 5 , Figure 7 and Figure 8As shown, the stirring mechanism 110 includes a vertical rod 111, a prism 112, a cylinder 113, stirring rods 114, balls 115, a slider 116, and a third gear 117. The upper end of the vertical rod 111 is fixedly connected to the slider 116, and the lower end of the vertical rod 111 is fixedly connected to the prism 112. The slider 116 is slidably connected to the guide groove 122 on the petal-shaped guide rail 121. The cylinder 113 is sleeved on the outside of the prism 112, and the inside of the cylinder 113 has a slot that matches the prism 112, so that the cylinder 113 can rotate synchronously with the prism 112 and slide axially relative to the prism 112. Multiple stirring rods 114 are mounted on the outer circumferential surface of the cylinder 113, and balls 115 are mounted on the bottom surface of the cylinder 113, with the balls 115 contacting the upper surface of the annular wave plate 140. The third gear 117 is fixedly sleeved on the vertical rod 111.

[0052] Specifically, because the guide groove 122 has a petal-shaped non-uniform radius trajectory, the slider 116 is subject to periodic radial constraint changes during movement, causing the vertical rod 111 to move back and forth towards and away from the shaft 131. By using the prism 112, the edges of the prism 112 can form an anti-rotation fit with the corresponding surface of the inner wall of the insert 113, allowing the insert 113 to rotate stably while maintaining axial freedom. The contact between the ball bearing 115 and the annular wave plate 140 transforms the bottom contour undulation into the axial undulation motion of the insert 113. The up and down movement of the insert 113 causes the stirring rod 114 to alternately cut into the mainstream area and near-bottom area at different heights, which can effectively reduce bottom deposition and stratification. Especially when there is incompletely dissolved substrate or subsequent crystallization slurry, it helps to maintain particle suspension and prevent the formation of dead material at the bottom. At the same time, the ball bearing 115 can significantly reduce contact friction, making the insert 113 less obstructed during undulation and running more smoothly.

[0053] like Figure 7 and Figure 8 As shown, the transmission mechanism 130 includes a shaft 131, a first gear 132, a rotating shaft 133, a second gear 134, a first hinge plate 135, and a second hinge plate 136.

[0054] The shaft 131 passes through the vessel cover 106 and is rotatably connected to the vessel cover 106. The upper end of the shaft 131 is fixedly connected to the power output shaft of the motor 108. The first gear 132 is fixedly sleeved on the shaft 131. The second gear 134 is fixedly sleeved on the rotating shaft 133. The second gear 134 meshes with both the first gear 132 and the third gear 117. The two ends of the first hinge plate 135 are hinged to the shaft 131 and the rotating shaft 133, respectively. The two ends of the second hinge plate 136 are hinged to the rotating shaft 133 and the vertical rod 111, respectively.

[0055] Specifically, since the vertical rod 111 does not move around a fixed radius but undergoes variable radius displacement due to the constraint of the petal-shaped guide rail 121, if the second gear 134 is directly and rigidly installed in a fixed position, the meshing relationship between the third gear 117 and the second gear 134 will inevitably become unstable when the vertical rod 111 approaches or moves away from the shaft 131. This invention utilizes the first hinge plate 135 and the second hinge plate 136 to form a movable connecting geometric chain, enabling the rotating shaft 133 to automatically adjust its position in space, thereby adapting to the positional changes of the vertical rod 111. In this geometric chain, the shaft 131 is equivalent to the active reference point, the vertical rod 111 is equivalent to the driven reference point, and the rotating shaft 133 is located between the two as a transitional meshing point. The first hinge plate 135 and the second hinge plate 136 provide a mechanism constraint with limited length but free rotation angle, allowing the second gear 134 to always be in a suitable position to participate in bilateral meshing.

[0056] like Figure 7 and Figure 8 As shown, the transmission mechanism 130 also includes a drive plate 137, which is fixedly connected to the shaft 131. A strip groove 138 is provided through the drive plate 137, and the vertical rod 111 passes through the strip groove 138 and is slidably connected to the strip groove 138.

[0057] Specifically, when the shaft 131 rotates, the drive plate 137 rotates synchronously, pushing the vertical rod 111 to move circumferentially around the shaft 131 under the limiting action of the strip groove 138. Since the vertical rod 111 is also constrained by the petal-shaped guide rail 121, the vertical rod 111 also undergoes radial reciprocating displacement during the circumferential rotation driven by the drive plate 137.

[0058] like Figure 2 and Figure 3 As shown, the reactor 100 also includes multiple support legs 105, a fixing frame 107, and a heat insulation base 151. The multiple support legs 105 are installed on the bottom surface of the reactor body 101 to stably support the entire unit. The fixing frame 107 is installed on the top surface of the reactor cover 106, and the motor 108 is mounted on the fixing frame 107. The heat insulation base 151 is installed on the outer surface of the reactor body 101, and a controller 152 is mounted on it. The controller 152 is used to control and display the operating status of the temperature control board, the motor 108, and the process stages.

[0059] Specifically, by setting up the fixing bracket 107, the motor 108 can be raised above the vessel cover 106, making the power input direction coaxial with the shaft 131, thus reducing transmission off-center load. By setting up the heat insulation seat 151, the controller 152 can be isolated from the high-temperature zone of the vessel body 101, which helps protect the electrical control components and improves operational safety.

[0060] Working principle: By opening the first feeding pipe 102, pretreated DL-leucine and a predetermined amount of water are added into the vessel body 101. Then, the motor 108 is started, and the motor 108 drives the transmission mechanism 130 via the shaft 131. The drive plate 137 starts to push the vertical rod 111 to rotate around the shaft 131. The first gear 132, the second gear 134 and the third gear 117 mesh synchronously, causing the vertical rod 111 and the insert 113 to rotate. The stirring rod 114 begins to initially disperse the system. When the slider 116 slides in the guide groove 122, the stirring trajectory covers areas of different radii. The ball bearing 115 rolls along the annular wave plate 140, causing the insert 113 to undulate up and down, thereby accelerating the wetting and dispersion of solid and liquid.

[0061] Then, an alkaline regulator is added into the vessel 101 through the second feeding pipe 103. The stirring mechanism 110 continues to operate, which promotes the rapid diffusion of the alkaline solution in the system and reduces local alkalinity changes. The temperature control board works according to the instructions of the controller 152 to control the temperature.

[0062] Once the system reaches the set pH level, the temperature of the reactor 101 is controlled by a temperature control plate to allow the reaction system inside the reactor to enter the low-temperature acylation zone. Acetic anhydride is then slowly added through the second feed pipe 103. As the stirring rod 114 continuously revolves, rotates, reciprocates radially, and undulates axially, the acetic anhydride can be rapidly dispersed after entering the system, avoiding the formation of a high-concentration area near the feed port.

[0063] During the acetic anhydride dropwise addition process, alkali solution is continuously added through the second feed pipe 103 to control the pH of the system. At this time, the petal-shaped guide rail 121 and the annular corrugated plate 140 work together to continuously exchange liquids at different heights and radii in the reactor, thereby improving the acylation selectivity.

[0064] After the reaction is complete, stop adding acetic anhydride and alkali solution, keep stirring mechanism 110 running for a period of time to homogenize the material, and then open discharge pipe 104 to discharge the acylation reaction solution to external impurity removal device.

[0065] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

[0066] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to specific implementations. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. A highly selective green acylation synthesis process for N-acetyl-DL-leucine, characterized in that, Includes the following steps: Step 1: Pre-dry the DL-leucine raw material to reduce fluctuations in the moisture content of the raw material and obtain pre-treated DL-leucine. Step 2: Add the pretreated DL-leucine to the reaction vessel (100), use water as the main solvent, add an alkaline regulator under stirring conditions, adjust the reaction system to weak alkalinity, and obtain the acylation reaction system. Step 3: Cool the acylation reaction system obtained in Step 2, and slowly add acetic anhydride to the acylation reaction system under stirring to carry out the acylation reaction, while maintaining the acylation reaction system as weakly alkaline during the addition of acetic anhydride; Step 4: After the acetic anhydride has been added, continue to keep the temperature high to allow DL-leucine to be fully converted, and obtain the acylation reaction solution. Step 5: Remove impurities from the acylation reaction solution to obtain a clear solution; Step 6: Acidify the clarified liquid to precipitate N-acetyl-DL-leucine and obtain crude slurry; Step 7: Perform solid-liquid separation and washing on the crude slurry to obtain crude N-acetyl-DL-leucine; Step 8: Recrystallize and purify the crude N-acetyl-DL-leucine. Step 9: Dry the recrystallized wet crystals to obtain N-acetyl-DL-leucine product.

2. The highly selective green acylation synthesis process for N-acetyl-DL-leucine according to claim 1, characterized in that, In step one, the pre-drying temperature is 40–80°C, and the moisture content of DL-leucine after pre-drying is no higher than 1.0 wt%. In step two, the alkaline regulator is one or more of sodium carbonate, sodium bicarbonate, and sodium hydroxide, and the pH of the acylation reaction system is controlled to be 7.5 to 9.

5. In step two, ethanol can also be added as a co-solvent, and the volume fraction of ethanol should not exceed 20% of the total volume of the reaction system.

3. The highly selective green acylation synthesis process for N-acetyl-DL-leucine according to claim 1, characterized in that, In step three, the acylation reaction temperature is 0–15°C, the molar ratio of DL-leucine to acetic anhydride is 1:1.00–1.20, the acetic anhydride is added over a period of 0.5–2 hours, and the pH of the reaction system is controlled at 7.5–9.5 during the addition process. In step four, the heat preservation reaction time is 0.5 to 3 hours, and the heat preservation reaction temperature is 5 to 25°C.

4. The highly selective green acylation synthesis process for N-acetyl-DL-leucine according to claim 1, characterized in that, In step six, the acidification treatment uses one of hydrochloric acid, acetic acid, or citric acid to adjust the pH of the system to 1.5–3.0, and crystallization occurs at 0–10°C. In step eight, the recrystallization purification uses water or a water-ethanol mixture as the solvent.

5. The highly selective green acylation synthesis process for N-acetyl-DL-leucine according to claim 1, characterized in that, The reaction vessel (100) used in step two includes: The vessel body (101) has a lid (106) installed on its top, and a motor (108) is provided above the lid (106). A stirring mechanism (110) is located inside the vessel body (101) and is used to stir the materials inside the vessel body (101); A petal-shaped guide rail (121) is installed on the bottom surface of the lid (106) and is slidably connected to the stirring mechanism (110); The transmission mechanism (130) is connected to the motor (108) and the stirring mechanism (110) for driving the stirring mechanism (110) to rotate when the motor (108) is running, and driving the stirring mechanism (110) to move along the petal-shaped guide rail (121); An annular wave plate (140) is installed on the inner bottom surface of the vessel body (101) and contacts the bottom of the stirring mechanism (110).

6. The highly selective green acylation synthesis process for N-acetyl-DL-leucine according to claim 5, characterized in that, The reactor (100) also includes: Multiple temperature control plates are embedded in the side wall of the vessel body (101); The first feeding pipe (102) is installed through the side wall of the vessel body (101); The second feeding pipe (103) is installed through the side wall of the vessel body (101); The discharge pipe (104) is installed through the bottom surface of the vessel body (101).

7. The highly selective green acylation synthesis process for N-acetyl-DL-leucine according to claim 5, characterized in that, The stirring mechanism (110) includes: A vertical rod (111) has a slider (116) and a prism (112) fixedly connected to its upper and lower ends respectively. The slider (116) is slidably connected to the guide groove (122) on the petal-shaped guide rail (121). The insert (113) has a slot inside that matches the prism (112), and the prism (112) is slidably connected to the insert (113); Multiple stirring rods (114) are all installed on the outer circumferential surface of the insert (113); A ball bearing (115) is installed on the bottom surface of the insert (113) and rolls in contact with the upper surface of the annular wave plate (140); The third gear (117) is fixedly sleeved on the vertical rod (111).

8. The highly selective green acylation synthesis process for N-acetyl-DL-leucine according to claim 7, characterized in that, The transmission mechanism (130) includes: A shaft (131) passes through the vessel cover (106) and is rotatably connected to the vessel cover (106), and its upper end is fixedly connected to the power output shaft of the motor (108); The first gear (132) is fixedly sleeved on the shaft (131); A rotating shaft (133) is fixedly fitted with a second gear (134), which meshes with the first gear (132) and the third gear (117). The first hinge plate (135) is hinged at both ends to the shaft (131) and the rotating shaft (133) respectively; The second hinge plate (136) is hinged at both ends to the pivot (133) and the vertical rod (111) respectively.

9. The highly selective green acylation synthesis process for N-acetyl-DL-leucine according to claim 8, characterized in that, The transmission mechanism (130) also includes: The drive plate (137) is fixedly connected to the shaft (131); A strip groove (138) is formed through the drive plate (137), and the vertical rod (111) passes through the strip groove (138) and is slidably connected to the strip groove (138).

10. The highly selective green acylation synthesis process for N-acetyl-DL-leucine according to claim 5, characterized in that, The reactor (100) also includes: Multiple support legs (105) are installed on the bottom surface of the vessel body (101); A mounting bracket (107) is installed on the top surface of the vessel lid (106), and the motor (108) is installed on the mounting bracket (107); A heat insulation seat (151) is installed on the outer surface of the vessel body (101), and a controller (152) is mounted on it.

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