Automated production method of pentose intermediate of fondaparinux sodium

Abstract

The present invention relates to a pentose intermediate of fondaparinux sodium. It uses an automated system with automatic sample loading and automatic sampling and monitoring to automate the production of the three components (D+EF+GH), obtaining the fully protected pentose intermediate of fondaparinux sodium (Formula I). ​​This automated synthesis of the pentose intermediate of fondaparinux sodium saves labor, improves efficiency and productivity, and provides high safety and reproducibility. Direct online monitoring facilitates real-time optimization and monitoring of the reaction. Automatic temperature control better meets the needs for temperature rise and fall. A "pre-activation" one-pot mode is adopted, reducing the number of isolation steps and simplifying the operation. The commonly used ester protecting group is used, resulting in high stereoselectivity and yield, and a commonly used deprotection method can be used. [Formula 1] JPEG2023553939000024.jpg53170

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceuticals, and particularly to an automated manufacturing method for a pentasaccharide intermediate of fondaparinux sodium.

Background Art

[0002] Heparin and sulfated heparin are very important linear sulfated polysaccharides among glycosaminoglycans, exist on the surface of most animal cells, and play important roles in various physiological processes, such as anticoagulation, anti-viral infection, inflammatory reaction, cell adhesion, cell growth regulation, lipid metabolism, tumor metastasis, etc. Fondaparinux sodium (Arixtra, Fondaparinμxsodiμm) is the smallest pentasaccharide domain that can specifically bind to antithrombin III. As shown in Figure 5, the structural formula is such that the five cyclic sugars are named in order as D, E, F, G, and H rings according to convention.

[0003] Fondaparinux sodium is currently the only artificially synthesized heparin - based oligosaccharide anticoagulant, which was launched in 2002. It is known as "Arixtra" as its trade name and is widely applied in orthopedic surgeries of the lower extremities. It can prevent the occurrence of venous thrombosis. The global market sales in 2017 were approximately $190 million. Compared with other low - molecular - weight heparins, it has significant anticoagulant activity, fewer side effects, and a longer half - life. However, due to the artificial synthesis with a total yield of less than 0.1% exceeding 50 steps, it has become the most expensive heparin - based pharmaceutical, severely restricting its wide application. Since the expiration of the patent in 2008, for the pentasaccharide fondaparinux, there are currently many convergent syntheses of (3 + 2) [ChemMedChem 2014, 9, 1071 - 1080; J. Org. Chem. 2016, 81, 162 - 184], (4 + 1) [Angew. Chem. Int. Ed. 2014, 53, 9876 - 9879.], one - pot three - component syntheses (Org. Chem. Front. 2019, 6, 3116 - 3120; Org. Lett. 2020, 22, 4638 - 4642.), and other extended syntheses and sulfation modifications by enzymatic methods and chemo - enzymatic methods (Science 2011, 334, 498 - 501). However, all of them need to be completed by highly specialized professional workers with training in special carbohydrate chemistry in a special carbohydrate chemistry laboratory, which is time - consuming and labor - intensive. This significantly increases the cost of obtaining fondaparinux. Therefore, better countermeasures and technologies for increasing the yield of the pentasaccharide of fondaparinux sodium are still needed. If it is possible to successfully obtain the fully protected pentasaccharide intermediate of fondaparinux efficiently and rapidly using an automated synthesis method, it will significantly reduce the manufacturing cost of fondaparinux sodium and bring important significance to its large - scale production and application.

Summary of the Invention

Problems to be Solved by the Invention

[0004] Based on this, an object of the present invention is to provide an automated production method of a pentose intermediate of fondaparinux sodium that saves labor, reduces human influence, and increases the yield of the pentose intermediate of fondaparinux sodium.

Means for Solving the Problems

[0005] To achieve the above object, the present invention provides the following aspects.

[0006] An automated production method of a pentose intermediate of fondaparinux sodium, including a reactor, a master computer, an inert gas device, a first activator container, a second activator container, a first sample container, a second sample container, a third sample container, an automatic sample loading system, a low-temperature circulation device, and a magnetic stirring device, wherein the method is applied to an automated production apparatus for a pentose intermediate of fondaparinux sodium. The inert gas device is respectively connected to the automatic sample loading system, the first activator container, the second activator container, the first sample container, the second sample container, and the third sample container. The automatic sample loading system is connected to the reactor. The automatic sample loading system, the low-temperature circulation device, and the magnetic stirring device are all connected to the master computer. The pentose intermediate of fondaparinux sodium has a structure represented by Formula I (named DEFGH-1).

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Advantages of the Invention

[0007] According to the specific embodiments provided in the present invention, the present invention discloses the following technical effects. The present invention discloses an automated manufacturing method for the pentose intermediate of fondaparinux sodium. By controlling an automatic sample loading system with a master computer to perform automatic sample loading, and controlling a detection device with the master computer to perform automatic on-line detection of the reactants in the reactor, the automated manufacturing of the pentose intermediate of fondaparinux sodium is realized, saving manpower, reducing artificial influence, increasing the yield of the pentose intermediate of fondaparinux sodium, and reducing the cost of the pentose intermediate of fondaparinux sodium.

[0008] The following is a brief description of the drawings that need to be used in the examples to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art. The following drawings are only some embodiments of the present invention, and it is obvious to those skilled in the art that other drawings can also be obtained based on these drawings without creative labor.

Brief Description of the Drawings

[0009]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Modes for Carrying Out the Invention

[0010] The following clearly and completely describes the technical aspects in the embodiments of the present invention with reference to the drawings in the embodiments of the present invention. It is obvious that the above embodiments are only a part of the embodiments according to the present invention, but not all of them. Based on the embodiments according to the present invention, any other embodiments obtained by those skilled in the art without creative labor belong to the protection scope of the present invention.

[0011] The present invention aims to provide an automated manufacturing method for pentose intermediates of fondaparinux sodium, which saves manpower, reduces artificial influence, increases the yield of pentose intermediates of fondaparinux sodium, and reduces costs.

[0012] In order to make the above objects, features, and advantages of the present invention clearer and easier to understand, the present invention will be further described in detail below by combining the drawings and specific embodiments.

[0013] Figure 1 is a schematic structural diagram of an automated manufacturing apparatus for pentose intermediates of fondaparinux sodium according to the present invention. Figure 2 is a schematic diagram of a detection apparatus according to the present invention. As shown in Figures 1-2, the present invention discloses an automated manufacturing apparatus for pentose intermediates of fondaparinux sodium, which includes a reactor 1, a master computer 33, an inert gas device 2, a first activator container 6-1, a first activator container 6-2, a first sample container 3, a second sample container 4, a third sample container 5, a switching valve, a syringe pump, a low-temperature circulation device 12, a magnetic stirring device 11, and a detection apparatus. The automatic sample loading system includes a switching valve and a syringe pump.

[0014] The inert gas device 2 is connected to the switching valve, the first activator container 6-1, the second activator container 6-2, the first sample container 3, the second sample container 4, and the third sample container 5 respectively. The first sample container 3, the second sample container 4, the third sample container 5, the first activator container 6-1 and the second activator container 6-2 are all connected to the switching valve. The switching valve is connected to the reactor 1 via a syringe pump. The detection device is connected to the reactor 1. The switching valve, the syringe pump, the low-temperature circulation device 12, the magnetic stirring device 11, and the detection device are all connected to the master computer 33. The low-temperature circulation device 12 provides a low-temperature environment for the reactor 1. The magnetic stirring device 11 is used to stir the reactants in the reactor 1.

[0015] The switching valve includes a first switching valve 7 and a second switching valve 8. The syringe pump includes a first syringe pump 9 and a second syringe pump 10. The range of the second syringe pump 10 is larger than that of the first syringe pump 9. The first switching valve 7 is connected to the first syringe pump 9. The second switching valve 8 is connected to the second syringe pump 10.

[0016] The automated manufacturing device further includes a flow meter 21 disposed in the pipeline between the syringe pump and the reactor 1. The automated manufacturing device further includes a pressure sensor 20 disposed in the pipeline between the syringe pump and the reactor 1.

[0017] The automated manufacturing device further includes an exhaust treatment device 13 and a waste liquid treatment device 14. The exhaust treatment device 13 and the waste liquid treatment device 14 are both connected to the reactor 1.

[0018] The inert gas device 2 is connected to the first port at the fourth solenoid valve 18 via a pressure regulating filter, and the inert gas device 2 is connected to the first port at the fifth solenoid valve 19 via a pressure regulating filter. The second port at the fourth solenoid valve 18 is connected to the first port at the first solenoid valve 15. The second port at the first solenoid valve 15 is connected to the tenth channel at the second switching valve 8. The third port at the first solenoid valve 15 is connected to the tenth channel at the first switching valve 7. The second port at the fifth solenoid valve 19 is connected to the first sample container 3, the second sample container 4, the third sample container 5, the first activator container 6-1, and the second activator container 6-2 respectively. The first sample container 3 is connected to the first channel at the first switching valve 7. The second sample container 4 is connected to the second channel at the first switching valve 7. The third sample container 5 is connected to the third channel at the first switching valve 7. The first activator container 6-1 is connected to the ninth channel at the first switching valve 7 and the ninth channel at the second switching valve 8 respectively. The second activator container 6-2 is connected to the eighth channel at the first switching valve 7 and the eighth channel of the second switching valve 8 respectively.

[0019] As shown in FIG. 3, the present invention discloses an automated manufacturing method of a pentose intermediate of fondaparinux sodium, wherein the pentose intermediate of fondaparinux sodium has a structure represented by Formula I (named DEFGH-1).

Chemical formula

[0020] The raw materials for producing the pentose intermediate of fondaparinux sodium include compound D-1, compound EF-1, and GH-1.

[0021] The method includes the following steps. That is, Step 101: Put compound D-1 having the structure represented by formula II into the first sample container 3.

Chemical formula

[0022] In the present invention, specifically, the compound D-1 preferably has the structure represented by formula II-1 (named compound D-3).

Chemical formula

[0023] Put the compound EF-1 having the structure represented by Formula III into the second sample container 4. [Chemical formula] Formula III (In the formula, R2 is a carboxyl group protecting group, preferably a methyl group (Me), R3 and R4 are independently acyl groups, preferably an acetyl group (Ac), SR8 is a thioglycoside-based leaving group, preferably a phenylthio group, p-methylphenylthio group, o-methylphenylthio group or 2-methyl-5-tert-butylphenylthio group, but not limited thereto, and Y is N3 or an amino group protected by various protecting groups.)

[0024] In the present invention, specifically, the compound EF-1 preferably has a structure represented by Formula III-1 (named compound EF-4). [Chemical formula] Formula III-1

[0025] Put the compound GH-1 having the structure represented by Formula IV into the third sample container 5. [Chemical formula] Formula IV (In the formula, R5 and R7 are independently acyl groups, preferably an acetyl group (Ac) or a benzoyl group (Bz), R6 is a carboxyl group protecting group, preferably a methyl group (Me), and Z is N3 or an amino group protected by various protecting groups.)

[0026] In the present invention, specifically, the compound GH-1 preferably has a structure represented by Formula IV-1 (named compound GH-2). [Chemical formula] Formula IV-1

[0027] A schematic diagram of the mechanism for generating the pentose intermediate DEFGH-1 of fondaparinux sodium in a one-pot three-component reaction of compound D-1, compound EF-1, and compound GH-1 is shown in Figure 6.

[0028] When compound D-1 preferably has a structure represented by formula II-1, compound EF-1 preferably has a structure represented by formula III-1, and compound GH-1 preferably has a structure represented by formula IV-1, the obtained pentose intermediate of fondaparinux sodium has a structure represented by formula I-1 (named compound DEFGH-2). JPEG0007716774000012.jpg49170Formula I-1

[0029] Step 102: Gas protection by filling the first sample container, the second sample container, the third sample container, the first activator container, the second activator container, and the reactor with an inert gas by an automatic sample loading system.

[0030] Step 103: Lower the temperature of the reactor by a low-temperature circulation device.

[0031] Step 104: Transport the compound D-1 to the reactor by an automatic sample loading system.

[0032] Step 105: Stir the compound D-1 in the reactor by a magnetic stirring device for preliminary drying.

[0033] Step 106: Sequentially transport the first activator in the first activator container and the second activator in the second activator container to the reactor by an automatic sample loading system, and perform preliminary activation on the compound D-1 for a first set time.

[0034] Step 107: Transport compound EF-1 to the reactor by an automatic sample loading system.

[0035] Step 108: Gradually heat the reactor to a programmed temperature by a low-temperature circulation device and carry out the reaction for a second set time. The second set time of the reaction is the programmed temperature rise time.

[0036] Step 109: Cool down the reactor by a low-temperature circulation device.

[0037] Step 110: Sequentially transport the first activator in the first activator container and the second activator in the second activator container to the reactor by an automatic sample loading system, and perform preliminary activation on the intermediate produced by the reaction of the compound D-1 and the compound EF-1 for a third set time.

[0038] Step 111: Transport compound GH-1 to the reactor by an automatic sample loading system.

[0039] Step 112: Gradually heat the reactor to a programmed temperature by a low-temperature circulation device and carry out the reaction for a fourth set time. The fourth set time of the reaction is the programmed temperature rise time.

[0040] Step 113: Transport a quench reaction solvent to the reactor by an automatic sample loading system to stop the reaction and obtain compound DEFGH-1.

[0041] Preferably, the first activator is p-toluenesulfonyl chloride, and the second activator is preferably silver trifluoromethanesulfonate.

[0042] When cooling down the reactor by a low-temperature circulation device, the cooling temperature is set to -75°C.

[0043] The rotation speed of the magnetic stirring device is set to 400 - 1000 rpm. The time for stirring the compound D-1 in the reactor by the magnetic stirring device is 1 - 300 min.

[0044] The automated manufacturing apparatus further includes a detection device, the detection device is connected to the pipeline of the reactor, and the detection device is electrically connected to the master computer.

[0045] In the method, after pre-activating the compound D-1 for a first set time, further detecting whether there is any residue of the compound D-1 by a detection device, and issuing an alarm if there is a residue. If there is a residue, step 107 is executed.

[0046] In the method, after pre-activating the intermediate generated by the reaction of the compound D-1 and the compound EF-1 for a third set time, further detecting whether there is any residue of the intermediate generated by the reaction of the compound D-1 and the compound EF-1 by a detection device, and issuing an alarm if there is a residue. If there is a residue, step 111 is executed.

[0047] In the method, the reactor is programmed to increase the temperature by the low-temperature circulation device, and after reacting for a fourth set time, further detecting whether there is any residue of the compound GH-1 by a detection device, and issuing an alarm if there is a residue. If there is a residue, step 113 is executed.

[0048] The solvent for reaction quenching is triethylamine.

[0049] After step 113, it also includes cleaning the pipeline, stopping refrigeration, stopping stirring, and closing the inert gas.

[0050] In the detection device, high performance liquid chromatography is used to detect the compound D-1, the compound EF-1 or the compound GH-1 in the reactor 1.

[0051] According to the reference (Org. Chem. Front. 2019, 63116 - 3120.), the manufacturing method of D-1 is that after the anomeric position of commercially available glucosamine D-2 is acetylated, thioglycoside is incorporated to obtain stable monosaccharide building block D-1. The manufacturing method of D-1 is as shown in Figure 8.

[0052] According to the reference (Org. Chem. Front. 2019, 63116 - 3120.), the manufacturing method of EF-1 is that from the commercialized diose intermediate EF-3, the lactone is ring-opened under the condition of tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) to obtain EF-4. Then, thioglycoside is incorporated into EF-4, and under the action of thiourea, the chloroacetyl group, which is a temporary protecting group, is removed to obtain the diose intermediate EF-1. The manufacturing method of EF-1 is as shown in Figure 9.

[0053] According to the reference (Org. Chem. Front. 2019, 63116 - 3120.), in the general deprotection and sulfonoxidation manufacturing method of the fully protected pentose intermediate DEFGH-1, DEFGH-1 first removes the acyl group and carboxyl group protecting groups under strongly alkaline conditions, or first removes the sterically hindered silyl protecting group under acidic conditions, and then removes the acyl group and carboxyl group protecting groups under strongly alkaline conditions. Then, it is O-sulfonated under heating conditions, and while removing the benzyl group and amino protecting groups by catalytic hydrogenation, the azide is reduced to an amino group, and finally the amino group is sulfonated to obtain fondaparinux sodium (DEFGH).

[0054] The monitoring and analysis module 32 in this example detects compound D-1, compound EF-1, or compound GH-1 in the reactor 1 by high performance liquid chromatography.

[0055] The present invention further discloses a computer-readable storage medium that stores computer-executable commands, and the computer-executable commands are set to execute an automated manufacturing method for the pentose intermediate of fondaparinux sodium.

[0056] The present invention discloses an automated manufacturing method for the pentose intermediate of fondaparinux sodium, which has the following advantages and beneficial effects compared with the prior art. That is, 1. The present invention realizes the automated manufacturing of the pentose intermediate of fondaparinux sodium, can save manpower, improve efficiency and productivity, and has high safety and reproducibility. 2. Direct on-line monitoring is possible, which facilitates the optimization and monitoring of the real-time state of the reaction. At the same time, the automatic temperature control can better meet the needs of the reaction for heating and cooling. 3. The "pre-activation" one-pot mode is adopted, reducing the number of isolations and making the operation convenient. 4. General ester protecting groups are selected, which have high stereoselectivity and yield, and general deprotection methods can be used, which is of great significance for reducing the production cost of fondaparinux sodium and large-scale production. Example:

[0057] Before automation, preferably, p-toluenesulfonyl chloride (p-TolSCl) and silver trifluoromethanesulfonate (AgOTf) are selected as the "pre-activation" system. Stock solutions of p-TolSCl (diluted in dichloromethane and connected to channel number 6) and AgOTf [(a mixed solution dissolved in toluene and dichloromethane (V / V = 3:1), connected to channel number 5)] are prepared and connected to the corresponding supply pipes. However, it is not limited to other "pre-activation" systems. Preferably, freshly activated 4A molecular sieves are pre-added to the reactor of the synthesis apparatus, and the reactor is sealed. Stock solutions of compound D-3 (connected to channel number 1), compound EF-4 (connected to channel number 2), and GH-2 (connected to channel number 3) (dissolved in a certain amount of dichloromethane) are prepared and connected to the corresponding supply pipes respectively. Dichloromethane dried as a solvent for sample loading or pipeline cleaning (connected to channel number 9) is prepared and connected to the corresponding pipeline. Triethylamine, a solvent for reaction quenching (diluted in dichloromethane and connected to channel number 8), is prepared and connected to the corresponding pipeline. Each switch of the synthesis apparatus is opened, and the software control program is started. After being automatically connected, a program for the automation project of the synthesis of the pentose intermediate of fondaparinux sodium is created (Table 1 below). Specific commands and parameters can be modified, deleted, increased, reordered, inserted, etc. according to the requirements of the reaction. Most commands have already been modularized and can be inserted according to needs, which is simple and convenient.

[0058] During automation, after creating the program, the project is loaded, and the "Start" button is clicked. The automated preparation apparatus automatically sequentially executes the program table of the created project, and the operator can temporarily stop or end the automated reaction process according to the actual situation.

[0059] Table 1 Procedure Table for the Automation Project of the Synthesis of the Pentose Intermediate of Fondaparinux Sodium

Table 1

[0060] Next, each command in Table 1 above will be described in detail. 1. Gas protection: (a) Control the opening of the fourth solenoid valve 18 and the fifth solenoid valve 19, control the communication between the first solenoid valve 15 and the first switching valve 7, control the communication between the 10-channel of the first switching valve 7 and the first syringe pump 9 (the first switching valve 7 - the first syringe pump 9), control the second solenoid valve 16 and the third solenoid valve 17 to communicate with the waste liquid bottle, control the opening of the flow meter 21, and perform V-shaped ventilation on the first syringe pump 9 at P1s (since a certain pressure is set in the gas source, the gas can pass through smoothly), and completely exhaust the air and other gases in the pipeline from the first switching valve 7 to the waste liquid; (b) Control the communication between the first solenoid valve 15 and the second switching valve 8, control the communication between the 10-channel of the second switching valve 8 and the second syringe pump 10 (the second switching valve 8 - the second syringe pump 10), perform V-shaped ventilation on the second syringe pump 10 at P2s, and completely exhaust the air and other gases in the pipeline from the second switching valve 8 to the waste liquid; (c) Control the third solenoid valve 17 to communicate with the reaction bottle, and completely exhaust the air and other gases in the pipeline between the second switching valve 8 and the reactor 1 (ensure that all pipelines are filled with argon gas and the flow meter 21 is open throughout the process), and continue to perform V-shaped ventilation on the second syringe pump 10 until it is commanded to close the gas pipeline. Otherwise, continue to ventilate so that the gas is discharged into the atmosphere (normal pressure) through the fourth solenoid valve 18 - the first solenoid valve 15 - the second switching valve 8 - the second syringe pump 10 - the second solenoid valve 16 - the third solenoid valve 17 - the reactor 1 - the gas. The V-shaped operation of the syringe pump means that the sample loading pipeline and the discharge pipeline of the syringe pump are controlled to be directly connected, and the gas does not pass through the suction and discharge processes of the syringe.

[0061] Control parameters: P1 is the V-shaped operation time (s) of the first syringe pump 9, and P2 is the V-shaped operation time (s) of the second syringe pump 10.

[0062] 2. Cooling start: Control the ultra-low temperature circulation device 12, start the refrigeration cooling and cycle according to the set temperature, and maintain the set temperature until the actual temperature reaches within the range of the set temperature (P1') ± the interval temperature (P2') or until a new command is received. Control parameters: P1' is the set temperature (°C), and P2' is the interval temperature (°C).

[0063] 3. Gas closing: Control the closing of the fourth solenoid valve 18 and the fifth solenoid valve 19. No control parameters.

[0064] 4. Building Block Transportation: Before executing this command, it is necessary to execute the gas protection command. First, based on the sum of the sample loading volume P3 and the compensation volume P4, the PLC determines which syringe pump the first solenoid valve 15 communicates with. If the sum of the volumes is greater than the syringe pump range of the small range, the first solenoid valve 15 communicates with the second syringe pump 10 of the large range. When the sum of the volumes is smaller than the syringe pump range of the small range, the first solenoid valve 15 is communicated with the first syringe pump 9 of the small range. When the second syringe pump 10 communicates with the corresponding second switching valve 8, different samples are extracted based on the channel number A1 of the second switching valve 8, and the second solenoid valve 16 and the third solenoid valve 17 are controlled to communicate with the waste liquid. The second switching valve 8 is controlled to change from the 10th channel to the A1 channel, the flow meter 21 is opened. The second syringe pump 10 first pumps the liquid at a flow rate of A2 μL / s to fill the volume P5 μL, and then discharges it into the waste liquid pipeline. After the pipeline from the second syringe pump 10 to the third solenoid valve 17 is filled with the sample, the second syringe pump 10 pumps the sum of the sample loading volume P3 and the compensation volume P4 from the A1 channel at a flow rate of A2 μL / s. When the sample extraction is just completed, the fifth solenoid valve 19 is controlled to close. While setting the flow meter 21 to zero, the third solenoid valve 17 is controlled to rotate towards the reactor 1. The flow meter 21 starts counting. When the target sample loading volume P3 is reached, the third solenoid valve 17 is reconverted to communicate with the waste liquid until the discharge of the syringe pump is complete. If the syringe pump has been completely discharged but the target sample loading volume has not been achieved, and there may be no sample solution in the liquid storage bottle or the sample solution is insufficient, an alarm is presented. Control parameters: A1 is the second switching valve channel number, A2 is the syringe pump flow rate, P3 is the sample loading volume, P4 is the compensation volume, and P5 is the filled volume.

[0065] 5. Pipeline Cleaning: This command is generally used after building block transportation and activator transportation and can also be used alone.

[0066] 5.1. Pipeline cleaning with gas pipeline to waste liquid (gas cleaning of pipeline): Control to open the fourth solenoid valve 18 and the fifth solenoid valve 19, control to connect the second solenoid valve 16, the third solenoid valve 17 and the waste liquid, control to connect the first solenoid valve 15 and the second switching valve 8, control to make the second switching valve 8 return to the 10-channel and connect it with the second syringe pump 10, and make the second syringe pump 10 perform V-type ventilation with B1s (let the gas pass through the fourth solenoid valve 18 - the first solenoid valve 15 - the first switching valve 7 - the first syringe pump 9 - the second solenoid valve 16 - the third solenoid valve 17). Blow gas to wash the pipeline from the second switching valve 8 to between the third solenoid valve 17 into the waste liquid. Control parameter: B1 is the V-type operation time (s) of the second syringe pump 10.

[0067] 5.2. Pipeline cleaning with solvent to waste liquid (liquid cleaning of pipeline): Control to switch the second switching valve 8 from the 10-channel to the A1 channel number (the solvent is generally dichloromethane), connect it with the second syringe pump 10, and the second syringe pump 10 pumps and discharges C4 μL of dichloromethane at a flow rate of C3 μL / s to wash the pipeline from the second switching valve 8 to the waste liquid and return it to the original position. Control parameters: A1 is the second switching valve channel number, C3 is the flow rate of the first syringe pump in μL / s, and C4 is the liquid washing volume in μL.

[0068] 5.3. Return to pipeline cleaning with gas pipeline to waste liquid (gas cleaning of pipeline): Control to return the second switching valve 8 from the P2 channel to the 10-channel and connect it with the second syringe pump 10, perform V-type ventilation on the first syringe pump 9 with B5 (s), blow gas to wash the pipeline from the second switching valve 8 to between the third solenoid valve 17 (the cleaning solvent inside is dichloromethane) into the waste liquid, and further return it to the original position. Control parameter: B5 is the V-type ventilation time (s) of the first syringe pump 9.

[0069] 5.4. Pipeline cleaning of the gas pipeline to the reactor 1 (gas cleaning of the pipeline): After ventilation of B5(S), rotate the third solenoid valve 17 from the waste liquid to the reactor 1, and blow gas to wash the pipeline from the third solenoid valve 17 to the reactor 1 until a new command comes in, so as to wash the pipeline into the reactor 1, and keep discharging the gas through the exhaust port of the reactor 1 (at this time, the first solenoid valve 15, the second solenoid valve 16, the third solenoid valve 17, the fourth solenoid valve 18 and the fifth solenoid valve 19 are opened, and the communication state with the reactor 1 is maintained through the second switching valve 8 and the second syringe pump 10). Control parameter: Use the parameter of B5.

[0070] 6. Start of stirring: The magnetic stirring function of the magnetic stirring device 11 starts stirring after setting the rotation speed to D1 (rpm) from the visualization digital display control interface, and setting the delay time to D2 (minutes, min), that is, after reaching the set rotation speed, start timing, and after the time reaches the set delay time, the command ends and the next command can be executed. Control parameters: D1 is the rotation speed, and D2 is the delay time (in minutes).

[0071] 7. Conveyor of Activator: This command is similar to the operation of the command for conveying building blocks, but the switching valve channels are connected to various activators. It is necessary to execute the gas protection command before executing this command. First, based on the sum of the sample loading volume P3 and the compensation volume P4, the PLC determines which syringe pump the first solenoid valve 15 communicates with. If the sum of the volumes is greater than the syringe pump range of the small range, the first solenoid valve 15 communicates with the second syringe pump 10 of the large range. If the sum of the volumes is less than the syringe pump range of the small range, the first solenoid valve 15 communicates with the first syringe pump 9 of the small range. When the second syringe pump 10 communicates with the corresponding second switching valve 8, different samples are extracted based on the channel number A1 of the second switching valve 8, and the second solenoid valve 16 and the third solenoid valve 17 are controlled to communicate with the waste liquid. The second switching valve 8 is controlled to change from channel 10 to channel A1, the flow meter 21 is opened, and the second syringe pump 10 first pumps the liquid at a flow rate of A2 μL / s to fill the volume P5 μL, and then discharges it into the waste liquid pipeline. After the pipeline from the second syringe pump 10 to the third solenoid valve 17 is filled with the sample, the second syringe pump 10 pumps the sum of the sample loading volume P3 and the compensation volume P4 from channel A1 at a flow rate of A2 μL / s. When the sample extraction is just completed, the fifth solenoid valve 19 is controlled to close, and while the flow meter 21 is set to zero, the third solenoid valve 17 is controlled to rotate to the reactor 1. The flow meter 21 starts counting. When the target sample loading volume P3 is reached, the third solenoid valve 17 is reconverted so that the discharge of the syringe pump is completely connected to the waste liquid until the syringe pump is completely discharged. If the target sample loading volume is not achieved when the syringe pump is completely discharged, an alarm is presented if there may be no sample solution in the liquid storage bottle or the sample solution is insufficient. Control parameters: A1 is the second switching valve channel number, A2 is the syringe pump flow rate, P3 is the sample loading volume, P4 is the compensation volume, and P5 is the filled volume.

[0072] 8. Activation Waiting: This command represents the waiting time for raw material activation after the activator is supplied. Since it is the "pre-activation" time, it is called activation waiting. The setting parameter is generally E1 (in minutes). It can also be used instead of the waiting time command and can be used repeatedly. Control Parameter: E1 is the activation waiting time (min).

[0073] 9. Reaction Time: This command is used to meet the changes in the reaction's temperature requirements and the reaction time, differentiating it from the start of temperature reduction. It mainly controls the ultra-low temperature circulation device 12. By controlling the temperature change of the ultra-low temperature circulation device 12, starting the operation according to the set temperature F1, when the actual temperature reaches within the range of the set temperature F1 ± the interval temperature F2, if timing starts, after meeting the delay time F3, the next command is executed. By repeatedly using the reaction time command, the purpose of programmed heating and cooling is achieved. Control Parameters: F1 is the set temperature (°C), F2 is the interval temperature (°C), and F3 is the delay time (in minutes).

[0074] 10. Reaction Waiting: This command represents the sampling and monitoring waiting time after the reaction has basically ended, differentiating it from activation waiting. The setting parameter is generally G1 (in minutes). It can also be used instead of the waiting time command and can be used repeatedly. Control Parameter: G1 is the sampling and monitoring waiting time (min).

[0075] 11. Stirring Stop: Controls the magnetic stirring to stop the stirring. No control parameter.

[0076] 12. Refrigeration Stop: Controls the low-temperature circulation device 12 to stop refrigeration and circulation.

[0077] Overall Analysis: In the entire automation process, the accuracy of sampling is the most demanding. Therefore, through the dual control of the syringe pump and the flow meter 21, the pipeline is flushed with appropriate commands to avoid cross-contamination, ensuring the stable operation of the entire system and accurate sample loading.

[0078] 13. Sampling monitoring: Generally performed after waiting for command activation of an automated manufacturing device. Sampling and Monitoring: The main function of this command is to automatically sample, load samples, clean the pipeline, and trigger the HPLC operation. The detection device will be as shown in Figure 2. First, control the third syringe pump to operate the reaction solution in the forward direction to a certain range at the sampling speed (H3, μL / s) and absorb it. This range is the sampling volume (H4, μL). First, air enters the syringe of the third syringe pump. The slide rail drives the stainless steel needle down to a certain sampling position (divided into H2, 1, 2, 3 stages), penetrates the sealed rubber gasket at the sampling port, contacts the needle with the reaction solution, and the residence time is the sampling time (H1, S, generally a very short time). Then, extract the reactor 1 by the upward movement of the slide rail (since the third syringe pump is always operating, there is no dripping of the reaction solution). The mechanical turntable rotates to a certain angle and then stops. The downward movement of the slide rail penetrates the liquid storage bottle mouth of the organic solvent (generally acetonitrile), contacts the needle with the organic solvent, and the residence time is the time to dilute the reaction solution, that is, the dilution time (H5, s, this time is much longer than the reaction solution contact time, and the slide rail can stop for a certain time). At this time, the organic solvent dilutes the reaction solution and enters the syringe of the third syringe pump together. The top of the syringe is air. The syringe is equivalent to the liquid storage bottle for diluting the reaction solution. Then, take out the organic solvent storage bottle by the upward movement of the slide rail, and the mechanical turntable continues to rotate to the waste liquid bottle. After moving down a certain distance (no need to penetrate), wait for reverse cleaning to the waste liquid.The third syringe pump continues the forward suction operation corresponding to dilution and uniform mixing. After the syringe has been sucked down a certain distance and reaches the set volume (X μL), it discharges the diluted reaction solution upward, controls to connect the electromagnetic valve and the high-pressure flow path switching valve, controls the high-pressure flow path switching valve to be in the sample loading state, performs sample loading with the power of the third syringe pump, and until the third syringe pump returns to its original position, the diluted reaction solution is injected into the loop (quantitative loop) of the high-pressure flow path switching valve. After injection, a short-circuit signal similar to a switch is given under the software control of the master computer to trigger the HPLC to start operating. The HPLC controls to switch the high-pressure flow path switching valve to the injection state, waits for a certain time, and then returns to the sample loading state to prepare for the next sample loading. After the 3 - 8 min operation of the HPLC is completed, a TXT report is immediately generated and output to the specified folder of the master computer. After the HPLC operation is completed, the column is automatically balanced, and it can wait for the next sampling monitoring. Simultaneously with the HPLC operation analysis, it controls to connect the electromagnetic valve and the organic solvent liquid storage bottle (intermediate bottle), controls the third syringe pump to suck the same volume of organic solvent (generally, acetonitrile may also be used) in the reverse direction at a constant speed, and flushes the slide rail pipe, the organic filter, and the stainless steel needle in the reverse direction into the waste liquid. The mechanical turntable rotates back to the organic solvent liquid storage bottle, the slide rail moves downward, penetrates the organic solvent liquid storage bottle, and is controlled to stay for a certain time. It controls the third syringe pump to suck the same volume of organic solvent in the forward direction, controls to connect the electromagnetic valve and the high-pressure flow path switching valve, pumps the organic solvent with the third syringe pump, and flushes the pipeline in the forward direction into the waste liquid bottle connected to the high-pressure flow path switching valve. Based on the above process, reverse cleaning and forward cleaning are each repeated once again, for a total of two times of reverse and forward cleaning, and the pipeline is basically cleaned cleanly. The slide rail returns to the position of reactor 1 upward to prepare for the next sampling and sample loading.Control parameters: H1 is the sampling time (s), H2 is the sampling position, H3 is the sampling speed (μL / s), H4 is the sampling volume, and H5 is the dilution time (s).

[0079] Up to this point, the hardware of the online monitoring system and its control scheme can operate stably according to the designed logical relationship. Whether the "Result Monitoring" command is used or not, after the operation of the "Sampling Monitoring" command ends, HPLC provides a state close to the real-time of the current reaction solution, facilitating the optimization and control of subsequent or next similar automated production of target molecules.

[0080] 14. The operation of the "Result Monitoring" command is to record, compare, feedback, and control whether the automatic operation continues by setting the logical relationship of data reporting in the "Online Monitoring" interface of the master computer. Generally, the "Result Monitoring" command is executed immediately after the "Sampling Monitoring" command. Of course, it can also be manually controlled independently. Its main function is to extract the latest TXT report, compare it with the previous TXT report for judgment. If it meets the prediction, continue the automation; if it exceeds the set limit, give an alarm, present the cause of the deadline exceed, and wait for manual processing. The user can choose to continue or stop the automated operation according to the actual situation.

[0081] During the automated operation, when the command "Sampling Monitoring" is executed, the "Result Monitoring" interface extracts the latest TXT report in the database folder as known data (shown in Figure 7) in advance, waits for the update of the TXT report, continuously updates the folder. When the operation of the command "Sampling Monitoring" ends, the master computer is designed to jump from the "Automatic Operation" interface to the "Result Monitoring" interface. If the HPLC operation has ended at this time and there is a new TXT report, the "Result Monitoring" interface automatically captures the latest data report as the collected data (as shown in Figure 7). If the HPLC operation has not ended, the "Result Monitoring" interface continuously updates the data folder, waits for the appearance of the latest data report as the collected data, and captures it (as shown in Figure 7).

[0082] To facilitate comparison and judgment, instead of extracting all the original data of the HPLC output, several of the most important and most common parameters including PEAK (number of peaks), R.TIME (retention time), AREA (peak area), HEIGHT (peak height), A / H (area / height), CONC. (concentration ratio) are extracted in the order of the original data (as shown in Figure 7). Among them, the criteria for comparison are the retention time and the concentration ratio, because different compounds have different retention times with the same analysis method, and the same compound basically has the same retention time with the same analysis method.

[0083] The specific logic relationship for designing the "online monitoring" interface is designed based on the reaction process of normal "pre-activation" one-pot automated manufacturing (shown in Figure 4). When extracting known data, first perform the first comparison and judgment of the magnitude of CONC., select the maximum value in CONC. as the concentration ratio of the unactivated "donor" or the "acceptor" just added after activation, and highlight this data row. This has a thioglycoside leaving group with strong ultraviolet absorption in both the donor and the acceptor. In normal one-pot glycosylation, by setting the start time of monitoring, it is possible to exclude the by-products with very low polarity and strong ultraviolet absorption generated after the activation of the thioglycoside by the activator. Moreover, the compounds with strong ultraviolet absorption are only the donor, the acceptor, and possible new products. After extracting the maximum value of CONC., find the corresponding R.TIME, expand the search range in the collected data with the corresponding R.TIME ± 0.05 (variable) to avoid the slight difference in retention time of the same compound under the same analysis method, search for the numerical value of the known data R.TIME ± 0.05 in the collected data, and perform the second comparison and judgment. If the corresponding data is not found, it means that the current state of the reaction solution does not have the "donor" or the "acceptor", or the "donor" or the "acceptor" has been completely activated or completely reacted and disappeared. If the R.TIME the same as the known data is detected from the collected data, it indicates that the current state of the reaction solution is either not activated or there are "donors" and "acceptors" that have not completely reacted. In this case, the corresponding CONC is detected. At this time, design the "comparison limit" parameter of CONC. (manually filled in based on experience and specific experimental requirements during the editing process of the automation program).) Continue the third comparison judgment. If the CONC. in the collected data retrieved is lower than the set "comparison limit" value, there are "donor" and "acceptor" that are not activated or not fully reacted, but the concentration ratio is very low, which is consistent with the expected reaction progress, and the automated manufacturing device can continue. If CONC. exceeds the set "contrast limit" value, it indicates that the remaining amounts of "donor" and "acceptor" that are not activated or not fully reacted exceed the prediction. When the master computer presents an alarm and highlights this data row, the automation waits for the user to process and pauses: If the user artificially selects to continue, the subsequent automation continues. When the "sampling monitoring" and "result monitoring" commands are being executed, the above-mentioned logic judgment is repeated until the entire automated manufacturing device completes it, and an automated manufacturing device report can be generated. If the user artificially processes and selects to stop, all subsequent program commands are terminated, and an automated manufacturing device report can also be generated, but only the building block information before stopping is shown.

[0084] Through three progressive automatic comparison judgments of the "online monitoring" interface of the above master computer, the reaction process can be clearly understood and tracked. If there are remaining alarm prompts for the "acceptor", the user can also perform the most reasonable processing based on the reaction state close to real-time.

[0085] Of course, the "sampling monitoring" and "result monitoring" commands are optional and may or may not be used.

[0086] After automation, the automatic synthesis results are saved, summarized, and analyzed. After disassembling the reactor, the reaction solution is filtered with diatomaceous earth, the filtrate is concentrated under reduced pressure, then isolated by column chromatography and preparative liquid chromatography to obtain the white solid compound DEFGH-2. The reactor is washed and dried to prepare for the next use. The building blocks of the liquid storage bottles and the reagents are recovered, washed, and dichloromethane is used instead of the used building blocks and reagent solutions. The "Sample Bottle Washing" command (parameters: switching valve channel number, flow rate (μL / s), sample loading volume (μL)) is set, and each sample storage liquid storage bottle is sequentially automatically washed to prepare for the next automated use. Finally, the "Gas Protection" command is executed to release the gas pressure in the pipeline, and the synthesizer is closed after closing the software. The differences in the automation of different target compounds mainly lie in the activation system, activation temperature, temperature and time during the reaction, and the execution of the overall automated operation is basically the same.

[0087] The automatic online monitoring of the present invention is based on the automatic sampling and sample loading equipment set in the self-developed synthesis device. After the automatic sampling and sample loading are completed, the master computer software automatically sends a short-circuit signal to trigger HPLC (Shimadzu LC-20A high-performance liquid chromatography for analysis), and sequentially receives command control operations according to batch processing. The specific analysis method is the commonly used Shimadzu LC-20A high-performance liquid chromatography for analysis. It is eluted using a 60%B - 100%B - 8.0 min gradient, monitored by an ultraviolet variable wavelength detector (254 nm and 280 nm), and the column is: Waters C18, 5 μm, 2.1 mm * 50 mm, and the mobile phases are: A H2O + 0.037% (v / v) TFA and B ACN + 0.018% (v / v) TFA.

[0088] Automated production method of pentose intermediate DEFGH-2 of fondaparinux sodium (Methyl 6-O-acetyl-3,4-di-O-benzyl-2-deoxy-2-azido-α-D-glucopyranosyl-(1→4)-(Methyl 2,3-di-O-benzyl-β-D-glucopyranosyluronate)-(1→4)-3,6-di-O-acetyl-2-deoxy-2-azido-α-D-glucopyranosyl-(1→4)-(methyl 2-O-acetyl-3-O-benzyl-α-L-idopyranosyluronate)-(1→4)-6-O-benzoyl-3-O-benzyl-2-deoxy-2-benzyloxycarbonylamino-α-D-glucopyranoside): Compound D-3 (49.80 mg, 0.096 mmol), compound EF-4 (60.1 mg, 0.08 mmol) and compound GH-2 (53.97 mg, 0.064 mmol) were prepared, and p-TolSCl (800 μL, 770 μL from diluting 90 μL to 5000 μL) / AgOTf [3000 μL, 2500 μL from dissolving 246.8 mg in a mixed solution of 10000 μL (8 mL toluene + 2 mL DCM)] was used. Through the general automated process of the activation system, isolation by column chromatography (petroleum ether / ethyl acetate, 2:1) and isolation by preparative liquid phase, a white compound 3-81 (73 mg, 0.03840 mmol, 60%) was obtained. Currently, when applied to the said automated production apparatus, the synthesis amount of pentose DEFGH-2 can already reach the gram-level gauge, and it is expected to continuously optimize the efficiency and scale-up. Figure 10 is a schematic diagram of the reaction mechanism for producing compound DEFGH-2 using compound D-3, compound EF-4, and compound GH-2 as raw materials. The characterization results of the obtained compound DEFGH-2 are as follows: R f = 0.12 (petroleum ether / ethyl acetate, 2:1); 11H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 7.3 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.40 - 7.30 (m, 30H), 7.26 - 7.20 (m, 5H), 5.55 (d, J = 3.8 Hz, 1H), 5.48 (d, J = 4.0 Hz, 1H), 5.40 - 5.35 (m, 1H), 5.07 - 5.01 (m, 5H), 4.90 (d, J = 5.9 Hz, 2H), 4.87 (d, J = 6.5 Hz, 1H), 4.86 (s, 1H), 4.85 - 4.83 (m, 2H), 4.82 (s, 1H), 4.80 (dd, J = 5.1, 2.8 Hz, 2H), 4.77 (d, J = 5.5 Hz, 2H), 4.71 (d, J = 10.9 Hz, 2H), 4.59 (d, J = 11.0 Hz, 2H), 4.48 (d, J = 11.8 Hz, 1H), 4.43 - 4.37 (m, 2H), 4.31 (d, J = 11.5 Hz, 1H), 4.25 - 4.18 (m, 2H), 4.09 (dd, J = 7.1, 4.7 Hz, 2H), 4.06 - 4.01 (m, 3H), 3.96 - 3.93 (m, 1H), 3.91 - 3.87 (m, 2H), 3.79 (s, 3H), 3.74 (dt, J = 15.4, 9.4 Hz, 2H), 3.63 (t, J = 9.7 Hz, 1H), 3.56 (s, 3H), 3.54 (d, J = 6.3 Hz, 2H), 3.46 (dd, J = 8.9, 8.1 Hz, 1H), 3.37 (s, 3H), 3.31 (dd, J = 10.4, 3.7 Hz, 1H), 3.22 (dd, J = 10.8, 3.4 Hz, 1H), 2.10 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H). 13CNMR(151 MHz, CDCl3) δ 170.66 (Ac, C=O), 170.11 (x2, Ac, C=O), 170.03 (Ac, C=O), 169.51 (COOMe, C=O), 168.39 (COOMe, C=O), 166.16 (Bz, C=O), 155.85 (Cbz, C=O), 138.29, 138.10, 137.57, 137.56, 137.49, 137.33, 136.30, 133.11, 129.86, 128.61, 128.56, 128.55, 128.52, 128.50, 128.44, 128.39, 128.28, 128.18, 128.09, 128.07, 128.05, 128.03, 127.99, 127.94, 127.91, 127.64, 127.58, 127.35, 127.24, 127.07, 103.28 (C-1), 98.77 (C-1), 98.09 (C-1), 97.62 (C-1), 97.57 (C-1), 83.78, 81.64, 80.14, 78.81, 77.03, 76.28, 75.79, 75.54, 75.22, 75.17, 74.99, 74.70, 74.42, 73.69, 73.25, 69.71, 69.61, 69.42, 69.34, 66.96, 63.26, 62.73, 62.22, 61.40, 60.87, 55.28, 54.60, 52.68, 52.22, 20.88, 20.86, 20.76, 20.69. HRMS(ESI + ) Anal. Calcd for C 98 H 107 N7O 32 Na [M+Na] + 1916.6853, found 1916.6826.

[0089] Each example in this specification adopts a progressive description, highlighting the differences between each example and other examples. For the same or similar parts between each embodiment, reference may be made to each other.

[0090] In this specification, the mechanisms and embodiments of the present invention have been described using specific examples. However, the above description of the embodiments is only used to assist in understanding the method and the gist of the present invention. Those skilled in the art will make changes in the specific embodiments and application scopes based on the technical idea of the present invention. As described above, the content of this specification should not be understood as a limitation to the present invention.

Explanation of Reference Numerals

[0091] 1, reactor; 2, inert gas device; 3, first sample container; 4, second sample container; 5, third sample container; 6-1, first activator container; 6-2, second activator container; 7, first switching valve; 8, second switching valve; 9, first syringe pump; 10, second syringe pump; 11, magnetic stirring device; 12, low-temperature circulation device; 13, exhaust treatment device; 14, waste liquid treatment device; 15, first solenoid valve; 16, second solenoid valve; 17, third solenoid valve; 18, fourth solenoid valve; 19, fifth solenoid valve; 20, pressure sensor; 21, flow meter; 30, sampling device; 31, power module; 32, monitoring and analysis module; 33, master computer

Claims

1. A method used in an automated production apparatus for pentose intermediates of fondaparinux sodium, comprising a reactor, a master computer, an inert gas device, a first activator container, a second activator container, a first sample container, a second sample container, a third sample container, an automatic sample loading system, a low-temperature circulation device, a magnetic stirring device, and a detection device, wherein the automatic sample loading system includes a switching valve and a syringe pump; the first sample container, the second sample container, the third sample container, the first activator container, and the second activator container are all connected to the switching valve; the switching valve is connected to the reactor via the syringe pump; the switching valve, the syringe pump, the low-temperature circulation device, the magnetic stirring device, and the detection device are all connected to the master computer; the switching valve includes a first switching valve and a second switching valve; the syringe pump includes a first syringe pump and a second syringe pump; the range of the second syringe pump is larger than that of the first syringe pump; the first switching valve is connected to the first syringe pump, and the second switching valve is connected to the second syringe pump; the automated production apparatus for pentose intermediates of fondaparinux sodium further includes a flow meter disposed in the pipeline between the syringe pump and the reactor, and a pressure sensor disposed in the pipeline between the syringe pump and the reactor; the detection device is connected to the pipeline of the reactor and electrically connected to the master computer; the inert gas device is connected to the switching valve, the first activator container, the second activator container, the first sample container, the second sample container, and the third sample container respectively; the low-temperature circulation device provides a low-temperature environment for the reactor, and the magnetic stirring device is used to stir the reactants in the reactor; the master computer controls the automatic sample loading system to perform automatic sample loading, and controls the detection device to perform automatic on-line detection of the reactants in the reactor; the pentose intermediate of fondaparinux sodium has a structure represented by Formula I (hereinafter named DEFGH-1), 【Chemical 1】 (wherein R １ is an acyl group or a silyl protecting group, R ２ and R ６ are independently carboxyl group protecting groups, R ３ and R ４ are independently acyl groups, R ５ and R ７ are independently acyl groups, X, Y, Z are independently N ３ or an amino group protected by various protecting groups.) The raw materials for producing the pentose intermediate of the fondaparinux sodium include Compound D-1, Compound EF-1, and GH-1. The method includes: placing Compound D-1 having a structure represented by Formula II in the first sample container; 【Chemical 2】 (wherein R １ is an acyl group or a silyl protecting group, SR ８ is a thioglycoside-based leaving group, and X is N ３ or an amino group protected by various protecting groups, ) placing Compound EF-1 having a structure represented by Formula III in the second sample container; [Chemical Formula 3] (In the formula, R ２ is a carboxyl group protecting group, R ３ and R ４ are independently acyl groups, SR ８ is a thioglycoside-based leaving group, and Y is N ３ or an amino group protected by various protecting groups.) placing Compound GH-1 having a structure represented by Formula IV in the third sample container; 【Chemical Formula 4】 (wherein R ５ and R ７ are each independently an acyl group, R ６ is a carboxyl group protecting group, and Z is N ３ or an amino group protected by various protecting groups), filling the first sample container, the second sample container, the third sample container, the first activator container, the second activator container, and the reactor with an inert gas by an automatic sample loading system for gas protection; lowering the temperature of the reactor by a low-temperature circulation device; conveying the Compound D-1 to the reactor by an automatic sample loading system; stirring the Compound D-1 in the reactor by a magnetic stirring device for preliminary drying; sequentially conveying the first activator in the first activator container and the second activator in the second activator container to the reactor by an automatic sample loading system, and performing preliminary activation on the Compound D-1 for a first set time; detecting whether there is any residue of the Compound D-1 by a detection device, and giving an alarm if there is any residue; conveying Compound EF-1 to the reactor by an automatic sample loading system; programmatically raising the temperature of the reactor by a low-temperature circulation device and performing a reaction for a second set time; lowering the temperature of the reactor by a low-temperature circulation device; sequentially conveying the first activator in the first activator container and the second activator in the second activator container to the reactor by an automatic sample loading system, and performing preliminary activation on the intermediate produced by the reaction between the Compound D-1 and the Compound EF-1 for a third set time; detecting whether there is any residue of the intermediate produced by the reaction between the Compound D-1 and the Compound EF-1 by a detection device, and giving an alarm if there is any residue; conveying Compound GH-1 to the reactor by an automatic sample loading system; programmatically raising the temperature of the reactor by a low-temperature circulation device and performing a reaction for a fourth set time; detecting whether there is any residue of the Compound GH-1 by a detection device, and giving an alarm if there is any residue; conveying a reaction quenching solvent to the reactor by an automatic sample loading system to stop the reaction and obtain Compound DEFGH-1. A method for the automated production of a pentose intermediate of fondaparinux sodium, characterized in that when the temperature of the reactor is decreased by a low-temperature circulation device, the temperature for temperature decrease is set to -75°C.

2. The method for the automated production of a pentose intermediate of fondaparinux sodium according to claim 1, characterized in that the first activator is p-toluenesulfonyl chloride and the second activator is silver trifluoromethanesulfonate.

3. The method for the automated production of a pentose intermediate of fondaparinux sodium according to claim 1, characterized in that the rotation speed of the magnetic stirring device is set to 400 to 1000 rpm.

4. The method for the automated production of a pentose intermediate of fondaparinux sodium according to claim 1, characterized in that the time for stirring compound D-1 in the reactor by the magnetic stirring device is 1 to 300 min.

5. The method for the automated production of a pentose intermediate of fondaparinux sodium according to claim 1, characterized in that the solvent for reaction quenching is triethylamine.

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