Method and system for controlled synthesis of 6-hydroxysphingosine and isomer thereof

Abstract

The invention relates to the technical field of automatic control, in particular to a method and system for controlling synthesis of 6-hydroxysphingosine and isomers thereof, and the system for controlling synthesis of 6-hydroxysphingosine and isomers thereof comprises an instruction loading module, a data acquisition module and a feedback control module, controlling to load a corresponding stage process instruction based on the triggered stage identifier, and judging whether the corresponding sensor and actuator are normal or not; controlling a corresponding sensor and an actuator to perform data acquisition based on the loaded stage process instruction, endowing the acquired synthetic data with a corresponding data identifier, and transmitting the acquired synthetic data; the synthesis stage matched with the current synthesis data is received and judged, the corresponding stage model is called for calculation and feedback control according to the judgment result, reaction conditions are mild, raw materials are easy to obtain, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of automation control technology, and in particular to a method and system for controlling the synthesis of 6-hydroxysphingosine and its isomers. Background Technology

[0002] 6-Hydroxysphingosine is a key intermediate in sphingolipid compounds and a precursor to 6-hydroxyceramide, an important component of the stratum corneum of the skin, and has significant application value in high-end cosmetics and pharmaceuticals. However, its industrial synthesis has always faced enormous challenges.

[0003] Currently, the reported synthetic methods are mainly total chemical synthesis routes. For example, Patrick Wisse et al. used compounds of formula 2 and 3 to construct the skeleton through olefin metathesis reactions in the presence of Grubbs II catalyst, such as... Figure 1 As shown; JS Yadav et al. prepared the key intermediate Formula 8 through a multi-step reaction, and then reacted it with S-Garner aldehyde (Formula 9), as shown. Figure 2 As shown. The above methods all involve more than a dozen chemical reactions, with low overall yields, which greatly increases production and time costs. Moreover, the synthesis of many key starting materials or intermediates (such as formulas 2, 3, and 8) required by the routes is difficult and there are no commercially available sources, further increasing the technical threshold and raw material costs.

[0004] More importantly, the synthesis process often requires reaction conditions such as ultra-low temperature, anhydrous and oxygen-free environments, or extremely demanding equipment requirements. These conditions can be controlled on a laboratory scale, but when scaled up for industrial production, there are huge safety risks, control challenges, and equipment investment pressures, resulting in poor process feasibility.

[0005] Market Gap: Due to the aforementioned issues, there is currently no mature and stable supply of 6-hydroxysphingosine products in the domestic and international markets. Therefore, it is extremely urgent to develop a 6-hydroxysphingosine synthesis process that features mild reaction conditions, readily available raw materials, and suitability for industrial production and marketization. Summary of the Invention

[0006] The purpose of this invention is to provide a method and system for the controlled synthesis of 6-hydroxysphingosine and its isomers, which has mild reaction conditions, readily available raw materials, and is suitable for industrial production.

[0007] To achieve the above objectives, in a first aspect, the present invention provides a method for the controlled synthesis of 6-hydroxysphingosine and its isomers, comprising the following steps: The corresponding stage process instruction is loaded based on the triggered stage identifier, and the corresponding sensors and actuators are checked for normal operation. Based on the loaded stage process instructions, the corresponding sensors and actuators are controlled to collect data, and the collected composite data is assigned a corresponding data identifier before being transmitted. Receive and determine the synthesis stage that matches the current synthetic data, and call the corresponding stage model for calculation and feedback control based on the determination result.

[0008] The method further includes: Based on the calculation results of the stage model, it is determined whether the current stage has been completed, and a stage identifier or a reaction completion symbol is generated according to the determination result.

[0009] The loading stage process instructions include: Phase 1 process instructions: Add sphingosine, the first reaction solvent, and 4-dimethylaminopyridine sequentially into a glass reaction flask. Cool the internal temperature to 0-10°C in an ice-water bath. Add acetic anhydride dropwise over 30 minutes. After the addition is complete, remove the ice-water bath and react at 20-30°C for 3-5 hours. After the reaction is completed by TLC monitoring, wash the reaction solution twice with NaCl aqueous solution. Concentrate the organic phase to dryness under reduced pressure at 40-50°C. Replace the organic phase twice with the crystallization solvent. Pulp at 0-10°C for 1 hour. Filter the solution. Dry the filtered solid at 40-50°C with forced air for 6 hours to obtain triacetylsphingosine. Phase 2 process instructions: Add the obtained triacetylsphingosine, the second reaction solvent, selenium dioxide, and acetic acid sequentially to a glass reaction flask, raise the temperature to 60-75℃ within 1-2 hours, and react for 10-15 hours; after the reaction is completed by TLC monitoring, add water for vacuum concentration; after concentration, add the second reaction solvent to separate the liquid, concentrate the obtained organic phase under vacuum, and use 100-200 mesh silica gel column chromatography. After vacuum concentration, triacetyl-6-hydroxysphingosine is obtained. Stage 3 process instructions: Triacetyl-6-hydroxysphingosine, the third reaction solvent, water, and deprotection reagent are added sequentially to a glass reaction flask. The temperature is increased to 75-85℃ for 1-2 hours, and the reaction is carried out for 5-6 hours. After the reaction is completed by TLC monitoring, the temperature is lowered to 20-30℃, and the mixture is extracted with 2-methyltetrahydrofuran. The organic phase is concentrated under reduced pressure at 45-55℃ and then subjected to silica gel column chromatography with a 100-200 mesh screen. 6-hydroxysphingosine is obtained by concentration under reduced pressure.

[0010] Specifically, the process involves controlling corresponding sensors and actuators to acquire data based on the loaded stage process instructions, and then transmitting the acquired composite data after assigning corresponding data identifiers, including: Based on the loaded stage process instructions, a corresponding staged data acquisition list is generated; Based on the phased data acquisition list, the corresponding data channels are opened, and the corresponding sensors and actuators are controlled to acquire data. After the collected synthetic data is assigned a preset data identifier, it is transmitted to the central server for caching.

[0011] The method further includes, during the process of controlling the corresponding sensors and actuators to acquire data: During the transition from Phase 1 to Phase 2, and from Phase 2 to Phase 3, the corresponding data channels are opened based on the phased data collection list and the acquired intermediate product quality reports, while the data channels of the previous phase are closed.

[0012] The process includes receiving and determining the current synthesis stage that matches the synthesized data, and then calling the corresponding stage model for calculation and feedback control based on the determination result. Extract the data identifiers from the synthetic data and perform a string comparison with the standard matching characters of the stage model; Based on the comparison results, the synthesized data is input into the corresponding stage model for calculation; Based on the output calculation results, corresponding stage control instructions are generated. At the same time, after the data identifier and the stage identifier are successfully matched, the instructions are transmitted based on the set execution mapping table.

[0013] After generating the stage identifier, the method further includes: Based on the generated stage identifier, an intermediate product quality report is generated by combining the corresponding synthesis data with the actual purity and yield data of the current stage.

[0014] Secondly, the present invention provides a system for controlling the synthesis of 6-hydroxysphingosine and its isomers, applicable to a method for controlling the synthesis of 6-hydroxysphingosine and its isomers as provided in the first aspect. The system for controlling the synthesis of 6-hydroxysphingosine and its isomers includes an instruction loading module, a data acquisition module, and a feedback control module. The instruction loading module is used to control the loading of the corresponding stage process instruction based on the triggered stage identifier, and at the same time determine whether the corresponding sensors and actuators are normal. The data acquisition module is used to control the corresponding sensors and actuators to acquire data based on the loaded stage process instructions, and to transmit the acquired synthetic data after assigning the corresponding data identifier. The feedback control module is used to receive and determine the current synthesis stage of the synthesized data, and call the corresponding stage model for calculation and feedback control based on the determination result.

[0015] Thirdly, the present invention provides a method for synthesizing 6-hydroxysphingosine and its isomers, applied to the method for controlled synthesis of 6-hydroxysphingosine and its isomers as provided in the first aspect, comprising the following steps: Sphingosine, the first reaction solvent, and 4-dimethylaminopyridine were added sequentially to a glass reaction flask. The internal temperature was lowered to 0-10°C in an ice-water bath. Acetic anhydride was added dropwise over 30 minutes. After the addition was complete, the ice-water bath was removed, and the reaction was carried out at 20-30°C for 3-5 hours. After the reaction was completed by TLC monitoring, the reaction solution was washed twice with NaCl aqueous solution. The organic phase was concentrated to dryness under reduced pressure at 40-50°C. The organic phase was replaced twice with crystallization solvent, and the mixture was slurried at 0-10°C for 1 hour. After filtration, the solid was dried under forced air at 40-50°C for 6 hours to obtain triacetylsphingosine. Triacetyl-6-hydroxysphingosine, the second reaction solvent, selenium dioxide, and acetic acid were added sequentially to a glass reaction flask. The temperature was raised to 60-75℃ within 1-2 hours, and the reaction was carried out for 10-15 hours. After the reaction was completed by TLC monitoring, water was added for concentration under reduced pressure. After concentration, the second reaction solvent was added and the mixture was separated. The organic phase was concentrated under reduced pressure and then purified by silica gel column chromatography using a 100-200 mesh column. After concentration under reduced pressure, triacetyl-6-hydroxysphingosine was obtained. Triacetyl-6-hydroxysphingosine, the third reaction solvent, water, and deprotection reagent were added sequentially to a glass reaction flask. The temperature was increased to 75-85℃ for 1-2 hours, and the reaction was carried out for 5-6 hours. After the reaction was completed by TLC monitoring, the temperature was lowered to 20-30℃, and the mixture was extracted with 2-methyltetrahydrofuran. The organic phase was concentrated under reduced pressure at 45-55℃ and then chromatographically analyzed on a 100-200 mesh silica gel column. The 6-hydroxysphingosine was obtained by concentration under reduced pressure.

[0016] The first reaction solvent is any one of dichloromethane, toluene, and tetrahydrofuran; The second reaction solvent is any one of tetrahydrofuran, dioxane, and dichloromethane; The deprotecting agent is any one of sodium hydroxide, hydrochloric acid, and sulfuric acid; The third reaction solvent is any one of methanol, ethanol, and dioxane.

[0017] This invention discloses a method and system for controlled synthesis of 6-hydroxysphingosine and its isomers. The system comprises an instruction loading module, a data acquisition module, and a feedback control module. Based on a triggered stage identifier, the system controls the loading of corresponding stage process instructions, while simultaneously determining whether the corresponding sensors and actuators are functioning correctly. Based on the loaded stage process instructions, the system controls the corresponding sensors and actuators to acquire data, assigns corresponding data identifiers to the acquired synthesis data, and then transmits the data. The system receives and determines the synthesis stage matched by the current synthesis data, and, based on the determination result, calls the corresponding stage model for calculation and feedback control. The reaction conditions are mild, the raw materials are readily available, and it is suitable for industrial production. Attached Figure Description

[0018] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below.

[0019] Figure 1 This is a schematic diagram of the steps for synthesizing 6-hydroxysphingosine from compounds of formula 2 and formula 3 provided by the present invention.

[0020] Figure 2 This is a schematic diagram of the steps for synthesizing 6-hydroxysphingosine from compounds of formula 8 and formula 9 provided by the present invention.

[0021] Figure 3 This is a schematic diagram of the synthesis steps in stage one provided by the present invention.

[0022] Figure 4 This is a schematic diagram of the synthesis steps in stage two provided by the present invention.

[0023] Figure 5 This is a schematic diagram of the synthesis steps in stage three provided by the present invention.

[0024] Figure 6 This is a schematic diagram of the steps of a method for controlling the synthesis of 6-hydroxysphingosine and its isomers provided in the first embodiment of the present invention.

[0025] Figure 7 This is a schematic diagram of the electronic device of the present invention. Detailed Implementation

[0026] Exemplary embodiments will now be described in detail, examples of which are illustrated in the accompanying drawings. When the following description relates to the drawings, unless otherwise indicated, the same numbers in different drawings represent the same or similar elements. The embodiments described in the following exemplary embodiments do not represent all embodiments consistent with this application.

[0027] The terminology used in this application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The singular forms “a,” “the,” and “the” used in this application and the appended claims are also intended to include the plural forms unless the context clearly indicates otherwise. It should also be understood that the term “and / or” as used herein refers to and includes any or all possible combinations of one or more of the associated listed items.

[0028] It should be understood that although the terms first, second, third, etc., may be used in this application to describe various information, such information should not be limited to these terms. These terms are only used to distinguish information of the same type from one another. For example, without departing from the scope of this application, first information may also be referred to as second information, and similarly, second information may also be referred to as first information. Depending on the context, the word "if" as used herein may be interpreted as "when," "when," or "in response to determination."

[0029] The first embodiment of this application is as follows: Please see Figure 6 This invention provides a method for controlled synthesis of 6-hydroxysphingosine and its isomers, comprising the following steps: S101. Based on the triggered stage identifier, control the loading of the corresponding stage process instruction, and at the same time determine whether the corresponding sensors and actuators are normal.

[0030] Specifically, based on the triggered stage identifier, a query is initiated to the central database to retrieve the corresponding basic process formula and load the corresponding stage process instruction. Simultaneously, based on the batch number, the intermediate product quality report generated in the previous stage (Stage 1 or Stage 2) is retrieved. Taking Stage 2 as an example, if the report shows that the purity of "Compound Formula 13" produced in Stage 1 is only 97.5% (slightly lower than the standard value of 99%), the Stage 2 model will predict that there may be more impurities in the reaction, increasing the risk of minor side reactions. In this case, the system may dynamically fine-tune the formula, for example, "slightly reducing the molar ratio of the oxidant selenium dioxide from 1:1.8 to 1:1.7" to reduce excessive oxidation side reactions caused by impurities. If the report shows that the yield in Stage 1 is significantly higher than expected, the system can determine that the raw material conversion is sufficient, giving it more confidence when loading the formula in Stage 2, and maintaining or optimizing the reaction rhythm. After the above corrections, the basic process formula and dynamically adjusted parameters are merged to generate the final stage process instruction for use.

[0031] After the stage process instructions are loaded, check and preset all relevant equipment. For example, in stage two, the system will preset the target value of the reactor temperature controller to 70°C.

[0032] Send the expected feed amount instruction to the selenium dioxide weighing module.

[0033] Configure an online ultraviolet spectrometer to start monitoring at a wavelength of 254 nm.

[0034] After all devices report a "ready" status, the system completes initialization and notifies the operator that "'Phase Two' is ready and execution can begin." It then proceeds to Step Two, initiating the data acquisition and control loop for this phase. This ensures that all sensors and actuators entering the current synthesis phase are functioning correctly. If a "ready" command cannot be generated, a warning message is issued, indicating a malfunction in the corresponding sensor or actuator. This allows for timely detection of faults before synthesis, preventing malfunctions from affecting the normal synthesis process.

[0035] The loaded stage process instructions include: Phase 1 Process Instructions: Add sphingosine, the first reaction solvent, and 4-dimethylaminopyridine sequentially to a glass reaction flask. Cool the flask to 0-10°C using an ice-water bath. Add acetic anhydride dropwise over 30 minutes. After the addition is complete, remove the ice-water bath and react at 20-30°C for 3-5 hours. Monitor the reaction progress by TLC. After the reaction is complete, wash the reaction solution twice with NaCl aqueous solution. Concentrate the organic phase to dryness under reduced pressure at 40-50°C. Replace the organic phase twice with a crystallization solvent. Pulverize at 0-10°C for 1 hour. Filter. The filtered solid was dried under forced air at 40-50°C for 6 hours to obtain triacetylsphingosine; wherein the first reaction solvent was dichloromethane, toluene, or tetrahydrofuran; the reaction temperature was 0-40°C, preferably 20-30°C; the molar ratio of sphingosine to acetic anhydride was 1:3-20, preferably 1:4-8; the crystallization solvent was petroleum ether or heptane; the weight ratio of sphingosine to crystallization solvent was 1:4-20, preferably 1:5-12; and the crystallization temperature was 0-20°C, preferably 0-10°C.

[0036] Stage Two Process Instructions: Add the obtained triacetylsphingosine, the second reaction solvent, selenium dioxide, and acetic acid sequentially to a glass reaction flask. Increase the temperature to 60-75℃ within 1-2 hours and react for 10-15 hours. After the reaction is complete (monitored by TLC), add water for vacuum concentration. After concentration, add the second reaction solvent and separate the liquid phase. Concentrate the obtained organic phase under vacuum and perform column chromatography using a 100-200 mesh silica gel column. After vacuum concentration, triacetyl-6-hydroxysphingosine is obtained. The second reaction solvent can be tetrahydrofuran, dioxane, dichloromethane, etc. The weight ratio of triacetylsphingosine to the reaction solvent is 1:1-20, preferably 1:5-12. The molar ratio of triacetylsphingosine to selenium dioxide is 1:1-5, preferably 1:1.5-3. The molar ratio of triacetylsphingosine to acetic acid is 1:2-8, preferably 1:3-7. The reaction temperature is 40-80℃, preferably 60-75℃.

[0037] Stage 3 process instructions: Add triacetyl-6-hydroxysphingosine, the third reaction solvent, water, and the deprotecting reagent sequentially to a glass reaction flask. Increase the temperature to 75-85℃ and react for 5-6 hours. After the reaction is complete (monitored by TLC), cool to 20-30℃, extract with 2-methyltetrahydrofuran, concentrate the organic phase under reduced pressure at 45-55℃, and precipitate by silica gel column chromatography (100-200 mesh). Concentrate under reduced pressure to obtain 6-hydroxysphingosine. The deprotecting reagent can be sodium hydroxide, hydrochloric acid, sulfuric acid, etc., with sodium hydroxide being preferred. The reaction solvent can be selected from methanol, ethanol, dioxane, etc., with ethanol being preferred; the weight ratio of triacetyl-6-hydroxysphingosine to the reaction solvent is 1:1~20, preferably 1:3~10; the weight ratio of triacetyl-6-hydroxysphingosine to water is 1:1~20, preferably 1:5~12; the weight ratio of triacetyl-6-hydroxysphingosine to sodium hydroxide is 1:1~3, preferably 1:1.1~1.5; the reaction temperature is 50~90℃, preferably 75~85℃; and the reaction time is 3~10h, preferably 4~8h.

[0038] An example illustrates the complete synthesis process of the above-mentioned stage process instructions: like Figure 3 As shown, 100g of sphingosine (Formula 12), 1000g of dichloromethane, and 50g of 4-dimethylaminopyridine were added sequentially to a glass reaction flask. The internal temperature was lowered to 0-10℃ in an ice-water bath. 153g of acetic anhydride was added dropwise over 30 minutes. After the addition was complete, the ice-water bath was removed, and the reaction was carried out at 20-30℃ for 3-5 hours. After the reaction was completed under TLC monitoring, the reaction solution was washed twice with 500 g of 10% NaCl aqueous solution each time. The organic phase was concentrated under reduced pressure (vacuum degree ≤ -0.07 MPa) at 40-50 °C to dryness, and then replaced twice with 300 g of petroleum ether each time. The concentrate was then slurried with 1000 g of petroleum ether at 0-10 °C for 1 h, filtered, and the filtrate was washed once with 300 g of ice-cold petroleum ether. The filtrate was then dried in a forced-air oven at 40-50 °C for 6 h to obtain 127 g of white solid of compound 13 triacetylsphingosine, with a molar yield of 89.4%. MS [M+H] + C 24 H 43 NO5 426.61.

[0039] like Figure 4As shown, 100g of compound 13, 700g of dioxane, 80g of selenium dioxide, and 250g of acetic acid were added sequentially to a glass reaction flask. The temperature was raised to 60-75℃ over 1-2 hours, and the reaction was carried out for 10-15 hours. After the reaction was completed by TLC monitoring, 300g of water was added, followed by vacuum concentration (≤-0.07 MPa). After concentration, 450g of dichloromethane was added, and the mixture was separated to obtain the organic phase. The organic phase was then concentrated under vacuum (≤-0.07 MPa) and analyzed using a 1kg 100-200 mesh silica gel column. After vacuum concentration (≤-0.07 MPa), 35.4g of a white solid of compound 14 (triacetyl-6-hydroxysphingosine) was obtained, with a yield of 47%. MS [M+H] + C 24 H 43 NO6441.61.

[0040] like Figure 5 As shown, 50 g of compound 14, 150 g of ethanol, 300 g of tap water, and 52.5 g of sodium hydroxide were added sequentially to a reaction flask. The temperature was raised to 75-85 °C for 1-2 hours, and the reaction was carried out for 5-6 hours. After the reaction was completed by TLC monitoring, the temperature was lowered to 20-30 °C, and the reaction solution was extracted with 500 g of 2-methyltetrahydrofuran. The organic phase was concentrated under reduced pressure at 45-55 °C (vacuum degree ≤ -0.07 MPa), and then subjected to 500 g of 100-200 mesh silica gel column chromatography. After concentration under reduced pressure (vacuum degree ≤ -0.07 MPa), 22.8 g of a racemic off-white solid of compound 1, 6-hydroxysphingosine was obtained, with a yield of 84%. 1 HNMR (400MHz, CDCl3) δ5.80(dd, 1H), 5.70 (dd,1H), 3.91~4.20(m,4H), 3.56~3.74(m,2H), 3.01(m,1H), 1.18~1.45(m,22H), 0.89(t,3H); MS[M+H] + C 18 H 37 NO3 316.27.

[0041] Alternatively, depending on the specific needs, preparative chromatography can be used to separate the racemic mixture to obtain high-purity R or S configurations of 6-hydroxysphingosine. The following are the preparative chromatographic separation conditions: Instrumentation: Preparative liquid chromatograph with UV detector; chromatographic column: C8 21.2×150mm 10μm; mobile phase: 0.2% phosphoric acid aqueous solution-acetonitrile (35:65); flow rate: 5mL / min; injection volume: 10ml; detection wavelength: 192nm.

[0042] S102. Based on the loaded stage process instructions, control the corresponding sensors and actuators to collect data, and then transmit the collected composite data after assigning the corresponding data identifier.

[0043] Specifically, based on the loaded stage process instructions, a corresponding staged data acquisition list is generated. This list clearly lists the data points that must be monitored in this stage and their detailed configurations. In Phase One (preparation of compound formula 13), the formulation emphasizes the acetylation reaction and crystallization process. Therefore, its data collection list will focus on including: Reactor internal temperature_1: Monitoring range 0-40℃, sampling frequency 1 time / second.

[0044] Acetic anhydride cumulative flow_1: Used for real-time calculation of the molar ratio with sphingosine.

[0045] Online near-infrared spectrometer_1: Absorbance at a specific wavelength, used to calculate reaction conversion rate.

[0046] Crystallization vessel temperature_1: Monitoring range 0-10℃.

[0047] Vacuum degree_1: Threshold ≤ -0.07 MPa when starting the concentration step.

[0048] In Phase Two (preparation of compound formula 14), the core of the formulation is allylic oxidation. The data collection list will be switched to: Reactor internal temperature_2: Monitoring range 60-75℃, sampling frequency 1 time / second. (Although it is the same physical sensor, it is logically identified as different data points) Selenium dioxide feed weight_2: Used to verify the molar ratio.

[0049] Online UV spectrometer_2: Monitors hydroxyl characteristic peaks at specific wavelengths and inputs oxidation kinetics models.

[0050] Acetic acid metering pump status_2: Monitoring the dosing process.

[0051] In Phase Three (Preparation of Compound Formula 1), the list shifts again, focusing on deprotection and separation: Reactor internal temperature_3 pH sensor_3: Real-time monitoring of deprotection progress.

[0052] Preparative online chromatographic detector_3: Monitors product elution peaks for separation purity assessment.

[0053] According to the data acquisition checklist, the data channels listed in the checklist are activated at the software level, while channels in other stages are disabled. This ensures that the data processing unit does not receive irrelevant or potentially interfering data. For intelligent instruments, the system performs advanced configuration. For example, at the beginning of stage two, the system sends a command to the online ultraviolet spectrometer via a communication protocol to set its monitoring wavelength to 254 nm as specified in the formula; and in stage three, the pH sensor's calibration point is confirmed.

[0054] All collected data is automatically tagged with a predefined data identifier the moment it is generated, and then transmitted to the central server for caching. This identifier contains at least: {data value, physical quantity name, stage ID, device number, timestamp}. For example, a temperature value in stage two is recorded as {68.5, "reactor internal temperature", "Stage_2", "Reactor-001", ...}.

[0055] The transition between phases is not a simple, instantaneous process, but a rigorous one that ensures data continuity and integrity. During the transition from Phase 1 to Phase 2, and from Phase 2 to Phase 3, the execution of the previous phase's "data acquisition list" is first halted, and all corresponding data channels are disabled. Then, the system loads the next phase's "data acquisition list" from the database. Based on the new list, the system sends new configuration parameters to the relevant smart sensors and actuators, such as setting a new wavelength for the spectrometer and a new target range for the temperature controller. After all sensors requiring activation report a "ready" status, the system officially starts the data acquisition process for the new phase. If any equipment malfunctions or fails to respond during this process, the system will issue an alarm and pause the transition. At any given time, only one phase's "data acquisition list" is allowed to be actively executing. This mechanism prevents data chaos caused by multiple phase acquisition lists running simultaneously due to network latency or overlapping instructions.

[0056] S103. Receive and determine the synthesis stage that matches the current synthesis data, and call the corresponding stage model for calculation and feedback control based on the determination result.

[0057] Specifically, the data identifier in the synthesized data is extracted and compared with the standard matching characters of the stage model. All the current synthesized data that successfully matches is input into the corresponding stage model. When the data identifier determines that the next stage has been entered, if the synthesized data from the previous stage is still received, the current synthesized data is marked as expired data and deleted.

[0058] The phase model includes three types: Phase 1 is the acetylation reaction monitoring model, Phase 2 is the allyl oxidation kinetic model, and Phase 3 is the deprotection reaction and separation monitoring model.

[0059] The acetylation reaction monitoring model in Phase 1 is a regression model based on spectral feature extraction. During the system development phase, a large amount of historical batch online near-infrared spectral data was collected, and the correspondence between it and the actual reaction conversion rate measured by offline analysis (such as HPLC) was established. Specific absorption peaks or band combinations most relevant to acetyl group formation in the spectrum were identified. Using multiple linear regression or machine learning algorithms (such as partial least squares regression PLSR), a mathematical prediction model was built from spectral feature values ​​to real-time conversion rate. The model receives real-time spectral data, immediately invokes the embedded mathematical relationships, and outputs a real-time predicted conversion rate. Simultaneously, it continuously monitors the temperature and material molar ratio within the reactor to ensure they remain within the range specified in the current formulation.

[0060] The kinetic model for the allylic oxidation in Stage 2 is a kinetic model that integrates mechanism and data-driven approaches. Based on the known reaction mechanisms of selenium dioxide allylic oxidation (such as the ene reaction and the [2,3]σ rearrangement reaction), a set of differential equations including the concentrations of major reactants and products is established as the model kernel. Using historical experimental data, key kinetic parameters (such as the reaction rate constant) in the model are accurately solved through optimization algorithms (such as genetic algorithms). The model uses real-time online ultraviolet spectral signals as a key observation variable and compares them with the product concentration trajectory predicted by the model. Algorithms such as Kalman filtering are used to fine-tune the model's predictions in real time to make them more consistent with the actual reaction conditions of the current batch. By combining the current reaction temperature, reactant concentration, and real-time ultraviolet spectral data, the remaining time required for the reaction to complete is dynamically predicted. It can identify the trend of reaction acceleration or deceleration in advance.

[0061] The Phase 3 deprotection reaction and separation monitoring model is a multi-sensor information fusion decision model based on chemical knowledge, defining a series of judgment rules. For example, when the pH value first drops rapidly and then enters a plateau period lasting more than 10 minutes, and the online chromatography detects that the peak area of ​​the target product no longer increases, the deprotection reaction is judged to be complete. The signal of the preparative chromatography online detector is trained for pattern recognition, enabling it to automatically identify the chromatographic peaks of the R and S configurations of 6-hydroxysphingosine. The model synchronously receives pH sensor data and chromatographic signals. It uses a built-in rule base for logical judgment to determine the reaction endpoint. In the separation stage, it analyzes the chromatogram in real time, calculates the real-time purity of the R / S configuration, and judges the separation effect.

[0062] Once each specialized analysis model has completed its calculations and judgments, it generates specific, executable control instructions based on the processing results.

[0063] Phase 1 Model: If the real-time predicted conversion rate is ≥ 95%, generate the following instruction: {Instruction: "Terminate reaction", Target: "Start post-processing program"} If the reactor internal temperature exceeds the range of 20-30℃, generate the following command: {Command: "Adjust Temperature", Target: "Reactor Temperature Control System", Setpoint: "25℃"} Phase Two Model: If the dynamic prediction indicates that the remaining time is significantly longer than expected, and there is room for temperature increase, generate the following instruction: {Instruction: "Slightly increase temperature", Target: "Reactor temperature control system", Adjustment value: "+2℃"} If the model detects a reaction standstill, it may generate the following instruction: {Instruction: "Suggest adding a co-oxidant", Target: "Operator alarm system", Suggested amount: "Trace TBHP"}.

[0064] Phase 3 Model: When the reaction completion rule is met, generate the following instruction: {Instruction: "End Deprotection", Target: "Reaction Termination and Cooling System"} Based on the real-time chromatographic purity, generate the following instruction: {Instruction: "Adjust mobile phase ratio", Target: "Preparative chromatography pump", Parameter: "Increase acetonitrile ratio to 67%"} to optimize separation.

[0065] Once a stage control command is generated, to ensure it is sent to the correct actuator, the system first verifies that the command's data identifier matches the stage identifier, rejecting any commands from inactive stages. This is a crucial lock to prevent misoperation. Simultaneously, an execution mapping table is preset. For example, in Stage_2, it only allows temperature control commands to be sent to the main reactor heating jacket, excluding operations on the crystallizer temperature control system. After a successful match between the data identifier and stage identifier, command transmission occurs based on the set execution mapping table, and the command is sent to the target actuator (such as a pump, valve, or heater). The system waits for status feedback from the actuator (e.g., "Temperature set to 72℃"), forming a complete control loop. If no confirmation signal is received, the system will retry or trigger an alarm.

[0066] If the current stage model predicts the end time of the current reaction stage, it can issue control commands to the next stage model in advance based on the predicted end time, and control operations such as preheating. The next stage model will continuously optimize the temperature setpoint for subsequent time periods based on the current reaction rate in order to seek the shortest reaction time while ensuring quality.

[0067] The method further includes: Based on the calculation results of the stage model, it is determined whether the current stage reaction is complete, and a stage identifier or reaction completion symbol is generated according to the determination result. Based on the generated stage identifier, combined with the corresponding synthesis data and the actual purity data and yield data of the current stage, an intermediate product quality report is generated.

[0068] Specifically, the completion of Stage 1 is marked by whether the "real-time predicted conversion rate" output by the acetylation reaction monitoring model consistently reaches or exceeds a preset threshold (e.g., ≥95%). The completion of Stage 2 is marked by whether the "reaction completion prediction value" output by the allylic oxidation kinetic model reaches a predetermined target (e.g., ≥99%), and whether its prediction reliability index is sufficiently high. The completion of Stage 3 is marked by the "reaction endpoint judgment" signal made by the deprotection reaction and separation monitoring model based on a rule base, and the "product purity meets the standard" signal obtained after preparative chromatographic separation.

[0069] Stage identifiers are generated based on the relevant signals from Stage 1 and Stage 2, and reaction completion symbols are generated based on the results of Stage 3. At the same time, all key data of the current stage (such as spectra, temperature curves, etc.) are collected and stored in the database to generate an intermediate product quality report.

[0070] Meanwhile, the generated stage identifier will trigger the loading of the corresponding stage process instructions until the reaction completion symbol is generated, marking the completion of the reaction, and all intermediate product quality reports will be summarized and stored.

[0071] This invention uses sphingosine as the starting material and proceeds through a three-step reaction involving amino and hydroxyl protection, allylic oxidation, and deprotection to obtain the racemic 6-hydroxysphingosine. This method features mild reaction conditions, simple post-processing, and strong feasibility for scale-up. This invention creatively utilizes a selenium dioxide oxidation system to introduce hydroxyl groups at the allylic position, thereby preparing 6-hydroxysphingosine and its isomers. This method simplifies reaction conditions and post-processing. This invention selectively protects the sphingosine to prevent the oxidation of amino and hydroxyl groups during allylic oxidation, thus reducing the generation of reaction impurities. This invention solves the problem of intelligent switching and resetting between upstream and downstream steps, ensuring that the quality data of upstream intermediates can automatically and effectively guide the optimization of downstream process parameters, thereby achieving full-process quality traceability and adaptive production. It can also automatically and accurately identify and distinguish different stages in the synthesis process and dynamically adjust monitoring and control strategies accordingly.

[0072] The second embodiment of this application is as follows: Please see Figure 4 This invention provides a system for controlling the synthesis of 6-hydroxysphingosine and its isomers, applicable to a method for controlling the synthesis of 6-hydroxysphingosine and its isomers as provided in the first embodiment. The system for controlling the synthesis of 6-hydroxysphingosine and its isomers includes an instruction loading module, a data acquisition module, and a feedback control module. The instruction loading module is used to control the loading of the corresponding stage process instruction based on the triggered stage identifier, and at the same time determine whether the corresponding sensors and actuators are normal. The data acquisition module is used to control the corresponding sensors and actuators to acquire data based on the loaded stage process instructions, and to transmit the acquired synthetic data after assigning the corresponding data identifier. The feedback control module is used to receive and determine the current synthesis stage of the synthesized data, and call the corresponding stage model for calculation and feedback control based on the determination result.

[0073] Regarding the system in the above embodiments, the specific ways in which each module performs operations have been described in detail in the embodiments related to the method, and will not be elaborated here.

[0074] For the system embodiments, since they basically correspond to the method embodiments, the relevant parts can be referred to in the description of the method embodiments. The device embodiments described above are merely illustrative. The units described as separate components may or may not be physically separate, and the components shown as units may or may not be physical units, that is, they may be located in one place or distributed across multiple network units. Some or all of the modules can be selected to achieve the purpose of this application according to actual needs. Those skilled in the art can understand and implement this without creative effort.

[0075] Accordingly, this application also provides an electronic device, comprising: one or more processors; a memory for storing one or more programs; and, when the one or more programs are executed by the one or more processors, causing the one or more processors to perform the method for controlled synthesis of 6-hydroxysphingosine and its isomers as described above. Figure 7 The diagram shown is a hardware structure diagram of any device with data processing capabilities, which is part of a system for controlling the synthesis of 6-hydroxysphingosine and its isomers provided in an embodiment of the present invention. Except for... Figure 7 In addition to the processor, memory, and network interface shown, any data processing device in the embodiment may also include other hardware depending on the actual function of the data processing device, which will not be described in detail here.

[0076] Accordingly, this application also provides a computer-readable storage medium storing computer instructions that, when executed by a processor, implement the method described above for the controlled synthesis of 6-hydroxysphingosine and its isomers. The computer-readable storage medium can be an internal storage unit of any data-processing device as described in any of the foregoing embodiments, such as a hard disk or memory. The computer-readable storage medium can also be an external storage device, such as a plug-in hard disk, smart media card (SMC), SD card, flash card, etc., equipped on the device. Furthermore, the computer-readable storage medium can include both internal storage units of any data-processing device and external storage devices. The computer-readable storage medium is used to store the computer program and other programs and data required by the data-processing device, and can also be used to temporarily store data that has been output or will be output.

[0077] Other embodiments of this application will readily occur to those skilled in the art upon consideration of the specification and practice of the disclosure herein. This application is intended to cover any variations, uses, or adaptations of this application that follow the general principles of this application and include common knowledge or customary techniques in the art not disclosed herein.

[0078] It should be understood that this application is not limited to the precise structure described above and shown in the accompanying drawings, and various modifications and changes can be made without departing from its scope.

Claims

1. A method for controlled synthesis of 6-hydroxysphingosine and its isomers, characterized in that, Includes the following steps: The corresponding stage process instruction is loaded based on the triggered stage identifier, and the corresponding sensors and actuators are checked for normal operation. Based on the loaded stage process instructions, the corresponding sensors and actuators are controlled to collect data, and the collected composite data is assigned a corresponding data identifier before being transmitted. Receive and determine the synthesis stage that matches the current synthetic data, and call the corresponding stage model for calculation and feedback control based on the determination result.

2. The method for controlled synthesis of 6-hydroxysphingosine and its isomers as described in claim 1, characterized in that, The method further includes: Based on the calculation results of the stage model, it is determined whether the current stage has been completed, and a stage identifier or a reaction completion symbol is generated according to the determination result.

3. The method for controlled synthesis of 6-hydroxysphingosine and its isomers as described in claim 1, characterized in that, The loaded stage process instructions include: Phase 1 process instructions: Add sphingosine, the first reaction solvent, and 4-dimethylaminopyridine sequentially into a glass reaction flask. Cool the internal temperature to 0-10°C in an ice-water bath. Add acetic anhydride dropwise over 30 minutes. After the addition is complete, remove the ice-water bath and react at 20-30°C for 3-5 hours. After the reaction is completed by TLC monitoring, wash the reaction solution twice with NaCl aqueous solution. Concentrate the organic phase to dryness under reduced pressure at 40-50°C. Replace the organic phase twice with the crystallization solvent. Pulp at 0-10°C for 1 hour. Filter the solution. Dry the filtered solid at 40-50°C with forced air for 6 hours to obtain triacetylsphingosine. Phase 2 process instructions: Add the obtained triacetylsphingosine, the second reaction solvent, selenium dioxide, and acetic acid sequentially to a glass reaction flask, raise the temperature to 60-75℃ within 1-2 hours, and react for 10-15 hours; after the reaction is completed by TLC monitoring, add water for vacuum concentration; after concentration, add the second reaction solvent to separate the liquid, concentrate the obtained organic phase under vacuum, and use 100-200 mesh silica gel column chromatography. After vacuum concentration, triacetyl-6-hydroxysphingosine is obtained. Stage 3 process instructions: Triacetyl-6-hydroxysphingosine, the third reaction solvent, water, and deprotection reagent are added sequentially to a glass reaction flask. The temperature is increased to 75-85℃ for 1-2 hours, and the reaction is carried out for 5-6 hours. After the reaction is completed by TLC monitoring, the temperature is lowered to 20-30℃, and the mixture is extracted with 2-methyltetrahydrofuran. The organic phase is concentrated under reduced pressure at 45-55℃ and then subjected to silica gel column chromatography with a 100-200 mesh screen. 6-hydroxysphingosine is obtained by concentration under reduced pressure.

4. The method for controlled synthesis of 6-hydroxysphingosine and its isomers as described in claim 1, characterized in that, Based on the loaded stage process instructions, the corresponding sensors and actuators are controlled to acquire data, and the acquired composite data is assigned a corresponding data identifier before transmission, including: Based on the loaded stage process instructions, a corresponding staged data acquisition list is generated; Based on the phased data acquisition list, the corresponding data channels are opened, and the corresponding sensors and actuators are controlled to acquire data. After the collected synthetic data is assigned a preset data identifier, it is transmitted to the central server for caching.

5. The method for controlled synthesis of 6-hydroxysphingosine and its isomers as described in claim 4, characterized in that, The method further includes the following steps during the data acquisition process, controlling the corresponding sensors and actuators: During the transition from Phase 1 to Phase 2, and from Phase 2 to Phase 3, the corresponding data channels are opened based on the phased data collection list and the acquired intermediate product quality reports, while the data channels of the previous phase are closed.

6. The method for controlled synthesis of 6-hydroxysphingosine and its isomers as described in claim 1, characterized in that, Receive and determine the current synthesis stage that matches the synthesized data, and call the corresponding stage model for calculation and feedback control based on the determination result, including: Extract the data identifiers from the synthetic data and perform a string comparison with the standard matching characters of the stage model; Based on the comparison results, the synthesized data is input into the corresponding stage model for calculation; Based on the output calculation results, corresponding stage control instructions are generated. At the same time, after the data identifier and the stage identifier are successfully matched, the instructions are transmitted based on the set execution mapping table.

7. The method for controlled synthesis of 6-hydroxysphingosine and its isomers as described in claim 2, characterized in that, After generating the stage identifier, the method further includes: Based on the generated stage identifier, an intermediate product quality report is generated by combining the corresponding synthesis data with the actual purity and yield data of the current stage.

8. A system for controlled synthesis of 6-hydroxysphingosine and its isomers, applied to the method for controlled synthesis of 6-hydroxysphingosine and its isomers as described in claim 1, characterized in that, The system for controlling the synthesis of 6-hydroxysphingosine and its isomers includes an instruction loading module, a data acquisition module, and a feedback control module. The instruction loading module is used to control the loading of the corresponding stage process instruction based on the triggered stage identifier, and at the same time determine whether the corresponding sensors and actuators are normal. The data acquisition module is used to control the corresponding sensors and actuators to acquire data based on the loaded stage process instructions, and to transmit the acquired synthetic data after assigning the corresponding data identifier. The feedback control module is used to receive and determine the current synthesis stage of the synthesized data, and call the corresponding stage model for calculation and feedback control based on the determination result.

9. A method for synthesizing 6-hydroxysphingosine and its isomers, applied to the method for controlled synthesis of 6-hydroxysphingosine and its isomers as described in claim 1, characterized in that, Includes the following steps: Sphingosine, the first reaction solvent, and 4-dimethylaminopyridine were added sequentially to a glass reaction flask. The internal temperature was lowered to 0-10°C in an ice-water bath. Acetic anhydride was added dropwise over 30 minutes. After the addition was complete, the ice-water bath was removed, and the reaction was carried out at 20-30°C for 3-5 hours. After the reaction was completed by TLC monitoring, the reaction solution was washed twice with NaCl aqueous solution. The organic phase was concentrated to dryness under reduced pressure at 40-50°C. The organic phase was replaced twice with crystallization solvent, and the mixture was slurried at 0-10°C for 1 hour. After filtration, the solid was dried under forced air at 40-50°C for 6 hours to obtain triacetylsphingosine. Triacetyl-6-hydroxysphingosine, the second reaction solvent, selenium dioxide, and acetic acid were added sequentially to a glass reaction flask. The temperature was raised to 60-75℃ within 1-2 hours, and the reaction was carried out for 10-15 hours. After the reaction was completed by TLC monitoring, water was added for concentration under reduced pressure. After concentration, the second reaction solvent was added and the mixture was separated. The organic phase was concentrated under reduced pressure and then purified by silica gel column chromatography using a 100-200 mesh column. After concentration under reduced pressure, triacetyl-6-hydroxysphingosine was obtained. Triacetyl-6-hydroxysphingosine, the third reaction solvent, water, and deprotection reagent were added sequentially to a glass reaction flask. The temperature was increased to 75-85℃ for 1-2 hours, and the reaction was carried out for 5-6 hours. After the reaction was completed by TLC monitoring, the temperature was lowered to 20-30℃, and the mixture was extracted with 2-methyltetrahydrofuran. The organic phase was concentrated under reduced pressure at 45-55℃ and then chromatographically analyzed on a 100-200 mesh silica gel column. The 6-hydroxysphingosine was obtained by concentration under reduced pressure.

10. The method for synthesizing 6-hydroxysphingosine and its isomers as described in claim 9, characterized in that, The first reaction solvent is any one of dichloromethane, toluene, and tetrahydrofuran; The second reaction solvent is any one of tetrahydrofuran, dioxane, and dichloromethane; The deprotecting agent is any one of sodium hydroxide, hydrochloric acid, and sulfuric acid; The third reaction solvent is any one of methanol, ethanol, and dioxane.

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