Method for preparing Fondaparinux sodium pentasaccharide intermediate compound 1 by using continuous flow microreactor

Abstract

The invention relates to the technical field of organic medicine synthesis, in particular to a method for preparing a fondaparinux sodium pentasaccharide intermediate compound 1 by using a continuous flow microreactor. The method comprises the following steps: dissolving a compound 2 in a solvent to obtain a homogeneous solution, pumping the homogeneous solution into a microreactor in a continuous flow microreactor in a hydrogen atmosphere, enabling the homogeneous solution to be in contact with a catalyst filled in the microreactor for reaction, and after the reaction is finished, freeze-drying the obtained reaction liquid to obtain the Fondaparinux sodium pentasaccharide intermediate compound 1. The method has the advantages of high yield and purity, controllable product quality, lower cost and higher safety. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of organic drug synthesis, and in particular to a method for preparing a fondaparinux sodium pentasaccharide intermediate compound 1 by using a continuous flow microreactor. Background Art

[0002] The Chinese chemical name of Fondaparinux sodium is: O-(2-deoxy-2-sulfonylamino-6-O-sulfonyl-α-D-pyranoglucopyranosyl)-(1→4)-O-β-D-pyranoglucopyranosyl-(1→4)-O-(2-deoxy-2-sulfonylamino-3,6-di-O-sulfonyl-α-D-pyranoglucopyranosyl)-(1→4)-O-(2-O-sulfonyl-α-L-iduronic acid)-(1→4)-2-deoxy-1-O-methyl-2-sulfonylamino-6-O-sulfonyl-α-D-pyranoglucopyranoside decasodium salt, and the chemical structure is as follows:

[0003]

[0004] Fondaparinux sodium is a pure chemically synthesized heparin pentasaccharide anticoagulant drug developed by Sanofi of France and currently available in many countries. It is clinically used to prevent and treat venous thrombosis and pulmonary embolism, with a recommended dose of 2.5 mg, once a day, by subcutaneous injection. With a bioavailability of 100% and a half-life of more than 17 hours, it is the preferred pillar product among heparin products.

[0005] The fondaparinux sodium pentasaccharide intermediate compound is a key intermediate in the synthesis of fondaparinux sodium. Its Chinese name is O-(2-deoxy-2-amino-6-O-sulfonyl-α-D-glucopyranosyl)-(1→4)-O-β-D-glucopyranosyl-(1→4)-O-(2-deoxy-2-amino-3,6-di-O-sulfonyl-α-D-glucopyranosyl)-(1→4)-O-(2-O-sulfonyl-α-L-iduronic acid)-(1→4)-2-deoxy-1-O-methyl-2-amino-6-O-sulfonyl-α-D-glucopyranosyl heptasodium salt. The chemical structure of the fondaparinux sodium pentasaccharide intermediate compound is shown in Compound 1:

[0006]

[0007] At present, in the prior art, the preparation method of fondaparinux sodium pentasaccharide intermediate compound mainly has the following process routes:

[0008] 1. Chinese patent publication number CN104144938A discloses a method for preparing a fondaparinux sodium pentasaccharide intermediate compound using palladium-carbon catalytic hydrogenation. The method uses a traditional reactor and stirs at room temperature or 60-65° C. under a certain pressure (such as 100 psi).

[0009] 2. Chinese patent publication number CN105473602A discloses a method for preparing a fondaparinux sodium pentasaccharide intermediate compound using a traditional autoclave. The method uses 10% palladium carbon as a solid catalyst and stirs at room temperature for 2 days to obtain a qualified target compound.

[0010] 3. Chinese patent publication number CN108148101A discloses a hydrogenation reduction method using palladium hydroxide as a catalyst. The method is carried out in an autoclave and the reaction is kept at 40° C. for 20 hours.

[0011] 4. Other documents that have been publicly reported for preparing fondaparinux sodium pentasaccharide intermediate compounds include AU2008200567A1, US8288515, US2012 / 0116066; Advances in carbohydrate chemistry and biochemistry, 2012, 67, 95-137; Chinese Journal of organic chemistry, 2012, 32, 1388-1400, etc.

[0012] The methods for preparing fondaparinux sodium pentasaccharide intermediate compounds that have been publicly reported in the literature all use traditional autoclave catalytic hydrogenation, which has the following disadvantages: (1) The process parameters of autoclave high-pressure catalytic hydrogenation have poor control precision, the production efficiency of intermittent production is low, and the safety hazards of process operation are high; (2) The catalyst is easily poisoned and inactivated by impurities such as sulfur and phosphorus, resulting in uncontrollable product quality; (3) The reaction process is less controllable, and local overheating or overcooling is prone to occur, resulting in poor uniformity of the reaction liquid, affecting product quality; (4) A long reaction time is required, generally between several hours and several days; (5) The service life of the catalyst is relatively short. For traditional methods, the above disadvantages are difficult to overcome, resulting in the production of fondaparinux sodium pentasaccharide intermediate compounds. Problems such as low synthesis yield, difficult to control product quality, high production cost and greater safety hazards have always existed. Therefore, it is urgent to improve the preparation strategy and develop new technologies to continuously and stably obtain high-quality products with reasonable cost, safe process and controllable quality.

[0013] At present, there is no literature report on the preparation of fondaparinux sodium pentasaccharide intermediate compounds using continuous flow microreaction technology. Summary of the invention

[0014] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a method for preparing fondaparinux sodium pentasaccharide intermediate compound 1 using a continuous flow microreactor with high yield and purity, controllable product quality, low cost and greater safety.

[0015] The present invention is achieved through the following technical solutions:

[0016] A method for preparing a fondaparinux sodium pentasaccharide intermediate compound 1 using a continuous flow microreactor, the method comprising the following steps: dissolving a compound 2 in a solvent to obtain a homogeneous solution, pumping the homogeneous solution into a microreactor in a continuous flow microreactor under a hydrogen atmosphere, contacting the homogeneous solution with a catalyst loaded in the microreactor to react, and after the reaction is completed, freeze-drying the obtained reaction solution to obtain the fondaparinux sodium pentasaccharide intermediate compound 1, and the fondaparinux sodium pentasaccharide intermediate compound 1 and compound 2 have the following structural formulas:

[0017]

[0018] In the formula, R1, R2, R3, R4, R5 and R6 are independently selected from phenyl and substituted phenyl.

[0019] Preferably, the solvent is water or a mixed solvent consisting of water and an organic solvent.

[0020] Preferably, the substituted phenyl group includes a halogenated phenyl group, such as a chlorophenyl group.

[0021] More preferably, the organic solvent is one or a combination of ethanol, propylene glycol, n-butanol, isopropanol, tert-butanol, polyethylene glycol, and dimethyl sulfoxide. Further preferably, the organic solvent is tert-butanol or isopropanol.

[0022] Preferably, the flow rate of the homogeneous solution pumped in is 1-60 mL / min, more preferably 10-40 mL / min.

[0023] Preferably, the hydrogen flow rate is controlled to be 100-600 mL / min, more preferably 200-400 mL / min.

[0024] Preferably, the catalyst is a mixture of one or more of palladium supported on activated carbon, palladium supported on alumina, palladium supported on polysilane and palladium hydroxide supported on activated carbon, and more preferably a mixture of one or two of palladium supported on activated carbon and palladium supported on alumina.

[0025] Preferably, the mass ratio of the catalyst to compound 2 is 0.46-2.33:1.

[0026] Preferably, the reaction temperature is 50-80°C, more preferably 50-70°C.

[0027] Preferably, the reaction time is 10-30s.

[0028] Preferably, after the reaction is completed, condensation is performed, and then gas-liquid separation is performed at a pressure of 0.1-5 MPa to obtain a reaction liquid.

[0029] Preferably, the microreactor is a fixed bed microreactor or a honeycomb microreactor, preferably a fixed bed microreactor.

[0030] More preferably, the microreactor has an inner diameter of 10-80 mm and a length of 0.3-1 m. Further preferably, the microreactor has an inner diameter of 10-60 mm and a length of 0.3-0.8 m.

[0031] More preferably, the material of the microreactor is one of Hastelloy, stainless steel, polytetrafluoroethylene or tempered glass, preferably Hastelloy or stainless steel.

[0032] The method for preparing fondaparinux sodium pentasaccharide intermediate compound 1 of the present invention is achieved through a continuous flow microreactor.

[0033] The continuous flow microreactor comprises a liquid storage tank, a hydrogen source, a fully automatic micro-reaction hydrogenation system and a freeze dryer. The liquid storage tank is connected to the A port of the fully automatic micro-reaction hydrogenation system, the hydrogen source is connected to the B port of the fully automatic micro-reaction hydrogenation system, the freeze dryer is connected to the D port of the fully automatic micro-reaction hydrogenation system, and the fully automatic micro-reaction hydrogenation system comprises a microreactor.

[0034] Preferably, the microreactor is filled with a catalyst.

[0035] The fully automatic micro-reaction hydrogenation system is composed of a metering pump, a preheater, a hydrogen flowmeter, a microreactor, a condenser and a gas-liquid separator. Port A is connected to the metering pump inlet, the metering pump outlet is connected to the preheater inlet, and the preheater outlet is connected to the microreactor; Port B is connected to the hydrogen flowmeter inlet, and the hydrogen flowmeter outlet is connected to the microreactor; the hydrogen flowmeter, the preheater and the microreactor are connected in parallel; the microreactor outlet is connected to the condenser inlet, and the condenser outlet is connected to the gas-liquid separator inlet; the gas-liquid separator has two outlets, which are respectively connected to ports C and D.

[0036] Furthermore, the condenser outlet is connected to the back pressure valve inlet, and the back pressure valve outlet is connected to the gas-liquid separator inlet.

[0037] The method of the present invention is carried out according to the following steps:

[0038] 1. Preparation of raw materials: At room temperature, compound 2 is dissolved in a solvent, and stirred continuously to prepare a homogeneous solution of a certain concentration, and placed in a liquid storage tank for standby use;

[0039] 2. Preparation of hydrogenation instrument: start-up, nitrogen replacement, flushing, hydrogen replacement;

[0040] 3. Reaction process: The liquid in the liquid storage tank is continuously pumped into the fully automatic micro-reaction hydrogenation system, and in the presence of continuously flowing hydrogen, it contacts with the catalyst loaded in the microreactor to react;

[0041] 4. Post-treatment: The reaction solution was freeze-dried by a freeze dryer to obtain the product compound 1.

[0042] Specifically, in the method of the present invention, compound 2 is dissolved in a solvent to obtain a homogeneous solution, which is placed in a liquid storage tank; the homogeneous solution in the liquid storage tank enters a metering pump through port A, and then is pumped into a preheater, and enters a microreactor after being preheated at 30-50°C by the preheater; a hydrogen source provides a continuous flow of hydrogen, which enters a hydrogen flowmeter through port B to control the hydrogen flow rate, and then enters the microreactor after flowing out of the hydrogen flowmeter; under the hydrogen atmosphere in the microreactor, the homogeneous solution contacts and reacts with a catalyst loaded in the microreactor, and after the reaction is completed, the obtained gas-liquid mixture is condensed through a condenser, and gas-liquid separation occurs in a gas-liquid separator, the obtained gas is discharged through port C, and the obtained reaction liquid flows out through port D and enters a freeze dryer for freeze drying, thereby obtaining fondaparinux sodium pentasaccharide intermediate compound 1.

[0043] The beneficial effects of the present invention are:

[0044] (1) The present invention provides a method for preparing fondaparinux sodium pentasaccharide intermediate compound 1 using continuous flow microreaction technology, which can significantly reduce production costs and is of great significance for its large-scale production and application.

[0045] (2) The present invention controls the reaction residence time, reaction temperature, and feed liquid flow rate to avoid excessively high local temperature or excessive concentration in the reaction system, thereby ensuring product quality;

[0046] (3) The present invention uses a solid catalyst loaded with palladium, which reduces the amount of catalyst used, prolongs the service life of the catalyst, and improves production efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 It is a schematic diagram of the structure of the continuous flow microreactor of the present invention. DETAILED DESCRIPTION

[0048] The present invention will be further described below in conjunction with specific embodiments, and the advantages and features of the present invention will become clearer as the description proceeds. However, these embodiments are exemplary only and do not constitute any limitation to the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solution of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the scope of protection of the present invention.

[0049] like Figure 1 As shown, the continuous flow microreactor of the present invention comprises a liquid storage tank, a hydrogen source, a fully automatic micro-reaction hydrogenation system and a freeze dryer, wherein the liquid storage tank is connected to the A port of the fully automatic micro-reaction hydrogenation system, the hydrogen source is connected to the B port of the fully automatic micro-reaction hydrogenation system, and the freeze dryer is connected to the D port of the fully automatic micro-reaction hydrogenation system. The microreactor is filled with a catalyst.

[0050] The fully automatic micro-reaction hydrogenation system consists of a metering pump, a preheater, a hydrogen flowmeter, a microreactor, a condenser and a gas-liquid separator. Port A is connected to the metering pump inlet, the metering pump outlet is connected to the preheater inlet, and the preheater outlet is connected to the microreactor; Port B is connected to the hydrogen flowmeter inlet, and the hydrogen flowmeter outlet is connected to the microreactor; the hydrogen flowmeter, preheater and microreactor are connected in parallel; the microreactor outlet is connected to the condenser inlet, and the condenser outlet is connected to the gas-liquid separator inlet; the gas-liquid separator has two outlets, which are connected to ports C and D respectively.

[0051] In addition, the fully automatic micro-reaction hydrogenation system is also provided with a back pressure valve, the condenser outlet is connected to the back pressure valve inlet, and the back pressure valve outlet is connected to the gas-liquid separator inlet.

[0052] The structural formula of compound 2 is as follows:

[0053]

[0054] Wherein, in the compound 2 used in Example 1-2, R1-R6 are all phenyl groups;

[0055] In the compound 2 used in Example 3, R1-R3 are phenyl groups, and R4-R6 are all chlorophenyl groups;

[0056] In the compound 2 used in Example 4-5, R1-R6 are all chlorophenyl.

[0057] Example 1

[0058] 5% Pd / Al2O3 (110g) was filled in a stainless steel microreactor (length 48cm, inner diameter 2cm). Compound 2 (43g, 0.02mol) was dissolved in a mixed solution of 1.5L water and tert-butyl alcohol (volume ratio 1:1) to obtain a raw material solution, and then the raw material solution was connected to the feed port A through a catheter, and the hydrogen was connected to the port B. The metering pump was adjusted to control the feed liquid flow rate to 20mL / min, the preheater temperature to 40℃, the temperature in the microreactor to 50℃, the hydrogen flow rate to 100mL / min, the back pressure value of the back pressure valve to 1.5MPa, and the reaction residence time to 15s. The gas-liquid mixture flowed out from the outlet of the microreactor, first cooled to room temperature through a condenser, then passed through a back pressure valve and a gas-liquid separator, the gas was discharged from port C, and the liquid flowed out through port D into a freeze dryer for collection and freeze drying, and finally an off-white solid product was obtained, which was the fondaparinux sodium pentasaccharide intermediate compound 1. Purity 95.2%, yield 98.1%.

[0059] The structural formula of compound 1 is as follows:

[0060]

[0061] Example 2

[0062] 5% Pd / Al2O3 (110g) was filled into a microreactor (length 48cm, inner diameter 2cm). Compound 2 (43g, 0.02mol) was dissolved in 1.5L water, and then the raw liquid was connected to the feed port A and the hydrogen was connected to the port B through a catheter. The metering pump was adjusted to control the feed liquid flow rate to 15mL / min, the preheater temperature to 40℃, the temperature in the microreactor to 50℃, the hydrogen flow rate to 80mL / min, the back pressure value of the back pressure valve to 1.5MPa, and the reaction residence time to 30s. The gas-liquid mixture flowed out from the outlet of the microreactor, first cooled to room temperature through the condenser, then passed through the back pressure valve and gas-liquid separator, the gas was discharged from the C port, and the liquid flowed out through the D port into the freeze dryer for collection and freeze drying, and finally a white solid product was obtained. The purity was 94.9% and the yield was 97.8%.

[0063] Example 3

[0064] 5% Pd / Al2O3 (20g) was filled in a microreactor (length 48cm, inner diameter 2cm). Compound 2 (43g, 0.02mol) was dissolved in a mixed solution of 1.5L water and tert-butyl alcohol (volume ratio 1:1), and then the raw material liquid was connected to the feed port A through a catheter, and the hydrogen was connected to the B port. The metering pump was adjusted to control the feed liquid flow rate to 30mL / min, the preheater temperature to 36℃, the temperature in the microreactor to 80℃, the hydrogen flow rate to 100mL / min, the back pressure value of the back pressure valve to 2MPa, and the reaction residence time to 10s. The gas-liquid mixture flowed out from the outlet of the microreactor, first cooled to room temperature through the condenser, then passed through the back pressure valve and gas-liquid separator, the gas was discharged from the C port, and the liquid flowed out through the D port into the freeze dryer for collection and freeze drying, and finally a white solid product was obtained. The purity was 95.5% and the yield was 96.6%.

[0065] Example 4

[0066] 5% Pd / C (20g) was filled in a microreactor (length 48cm, inner diameter 2cm). Compound 2 (43g, 0.02mol) was dissolved in a mixed solution of 1.5L water and tert-butyl alcohol (volume ratio 1:1), and then the raw material liquid was connected to the feed port A through a catheter, and the hydrogen was connected to the B port. The metering pump was adjusted to control the feed liquid flow rate to 20mL / min, the preheater temperature to 36°C, the temperature in the microreactor to 50°C, the hydrogen flow rate to 360mL / min, the back pressure value of the back pressure valve to 2MPa, and the reaction residence time to 20s. The gas-liquid mixture flowed out from the outlet of the microreactor, first cooled to room temperature through the condenser, then passed through the back pressure valve and gas-liquid separator, the gas was discharged from the C port, and the liquid flowed out through the D port into the freeze dryer for collection and freeze drying, and finally a white solid product was obtained. The purity was 96.1% and the yield was 97.6%.

[0067] Example 5

[0068] 5% Pd / Al2O3 (20g) was filled in a microreactor (length 48cm, inner diameter 2cm). Compound 2 (43g, 0.02mol) was dissolved in a mixed solution of 1.5L water and ethanol (volume ratio 1:1), and then the raw liquid was connected to the feed port A through a catheter, and the hydrogen was connected to the B port. The metering pump was adjusted to control the feed liquid flow rate to 20mL / min, the preheater temperature to 32℃, the temperature in the microreactor to 50℃, the hydrogen flow rate to 80mL / min, the back pressure value of the back pressure valve to 2MPa, and the reaction residence time to 15s. The gas-liquid mixture flowed out from the outlet of the microreactor, first cooled to room temperature through the condenser, then passed through the back pressure valve and gas-liquid separator, the gas was discharged from the C port, and the liquid flowed out through the D port into the freeze dryer for collection and freeze drying, and finally a white solid product was obtained. The purity was 96.2% and the yield was 98.1%.

[0069] Comparative Example 1: This comparative example is a method for preparing a key intermediate compound of fondaparinux sodium using a conventional high-pressure reactor.

[0070] Compound 2 (43 g, 0.02 mol), 10% Pd / Al2O3 (60 g) and 860 mL of a mixed solution of water and tert-butyl alcohol (volume ratio 1:1) were added to a 2L autoclave, hydrogen was introduced, and the mixture was stirred at 65°C and 2 MPa for 40 h. The mixture was filtered and concentrated to dryness under reduced pressure. An appropriate amount of acetonitrile was added for pulping and filtered to obtain an off-white solid product. The purity was 81.4% and the yield was 85.2%.

[0071] The difference between Comparative Example 2 and Example 5 is that the reaction temperature is different, specifically:

[0072] 5% Pd / Al2O3 (20g) was filled in a microreactor (length 48cm, inner diameter 2cm). Compound 2 (43g, 0.02mol) was dissolved in a mixed solution of 1.5L water and ethanol (volume ratio 1:1), and then the raw material liquid was connected to the feed port A through a catheter, and the hydrogen was connected to the B port. The metering pump was adjusted to control the feed liquid flow rate to 20ml / min, the preheater temperature to 32℃, the temperature in the microreactor to 40℃, the hydrogen flow rate to 80ml / min, the back pressure value of the back pressure valve to 2MPa, and the reaction residence time to 15s. The gas-liquid mixture flowed out from the outlet of the microreactor, first cooled to room temperature through the condenser, then passed through the back pressure valve and gas-liquid separator, the gas was discharged from the C port, and the liquid flowed out through the D port into the freeze dryer for collection and freeze drying, and finally a white solid product was obtained. The purity was 90.5% and the yield was 87.7%.

[0073] The difference between Comparative Example 3 and Example 5 is that the reaction temperature is different, specifically:

[0074] 5% Pd / Al2O3 (20g) was filled in a microreactor (length 48cm, inner diameter 2cm). Compound 2 (43g, 0.02mol) was dissolved in a mixed solution of 1.5L water and ethanol (volume ratio 1:1), and then the raw material liquid was connected to the feed port A through a catheter, and the hydrogen was connected to the B port. The metering pump was adjusted to control the feed liquid flow rate to 20ml / min, the preheater temperature to 32℃, the temperature in the microreactor to 85℃, the hydrogen flow rate to 80ml / min, the back pressure value of the back pressure valve to 2MPa, and the reaction residence time to 15s. The gas-liquid mixture flowed out from the outlet of the microreactor, first cooled to room temperature through the condenser, then passed through the back pressure valve and gas-liquid separator, the gas was discharged from the C port, and the liquid flowed out through the D port into the freeze dryer for collection and freeze drying, and finally a white solid product was obtained. The purity was 86.3% and the yield was 75.2%.

[0075] The difference between Comparative Example 4 and Example 5 is that different catalysts are used, specifically:

[0076] 5% Ni / SiO2 (20g) was filled in a microreactor (length 48cm, inner diameter 2cm). Compound 2 (43g, 0.02mol) was dissolved in a mixed solution of 1.5L water and ethanol (volume ratio 1:1), and then the raw liquid was connected to the feed port A through a catheter, and the hydrogen was connected to the B port. The metering pump was adjusted to control the feed liquid flow rate to 20mL / min, the preheater temperature to 32℃, the temperature in the microreactor to 50℃, the hydrogen flow rate to 80mL / min, the back pressure value of the back pressure valve to 2MPa, and the reaction residence time to 15s. The gas-liquid mixture flowed out from the outlet of the microreactor, first cooled to room temperature through the condenser, then passed through the back pressure valve and gas-liquid separator, the gas was discharged from the C port, and the liquid flowed out through the D port into the freeze dryer for collection and freeze drying, and finally a white solid product was obtained. The purity was 85.4% and the yield was 87.5%.

[0077] The difference between Comparative Example 5 and Example 5 is that the reaction residence time is different, specifically:

[0078] 5% Pd / Al2O3 (20g) was filled into a microreactor (length 48cm, inner diameter 2cm). Compound 2 (43g, 0.02mol) was dissolved in a mixed solution of 1.5L water and ethanol (volume ratio 1:1), and then the raw liquid was connected to the feed port A through a catheter, and the hydrogen was connected to the B port. The metering pump was adjusted to control the feed liquid flow rate to 20mL / min, the preheater temperature to 32℃, the temperature in the microreactor to 50℃, the hydrogen flow rate to 80mL / min, the back pressure value of the back pressure valve to 2MPa, and the reaction residence time to 5s. The gas-liquid mixture flowed out from the outlet of the microreactor, first cooled to room temperature through the condenser, then passed through the back pressure valve and gas-liquid separator, the gas was discharged from the C port, and the liquid flowed out through the D port into the freeze dryer for collection and freeze drying, and finally a white solid product was obtained. The purity was 75.6% and the yield was 48.8%.

[0079] The difference between Comparative Example 6 and Example 5 is that the reaction residence time is different, specifically:

[0080] 5% Pd / Al2O3 (20g) was filled in a microreactor (length 48cm, inner diameter 2cm). Compound 2 (43g, 0.02mol) was dissolved in a mixed solution of 1.5L water and ethanol (volume ratio 1:1), and then the raw material liquid was connected to the feed port A through a catheter, and the hydrogen was connected to the B port. The metering pump was adjusted to control the feed liquid flow rate to 20mL / min, the preheater temperature to 32℃, the temperature in the microreactor to 50℃, the hydrogen flow rate to 80mL / min, the back pressure value of the back pressure valve to 2MPa, and the reaction residence time to 45s. The gas-liquid mixture flowed out from the outlet of the microreactor, first cooled to room temperature through the condenser, then passed through the back pressure valve and gas-liquid separator, the gas was discharged from the C port, and the liquid flowed out through the D port into the freeze dryer for collection and freeze drying, and finally a white solid product was obtained. The purity was 92.6% and the yield was 85.1%.

[0081] The difference between Comparative Example 7 and Example 5 is that the feed amount is different, specifically:

[0082] 5% Pd / Al2O3 (20g) was filled in a microreactor (length 48cm, inner diameter 2cm). Compound 2 (43g, 0.02mol) was dissolved in a mixed solution of 1.5L water and ethanol (volume ratio 1:1), and then the raw liquid was connected to the feed port A through a catheter, and the hydrogen was connected to the B port. The metering pump was adjusted to control the feed liquid flow rate to 70mL / min, the preheater temperature to 32℃, the temperature in the microreactor to 50℃, the hydrogen flow rate to 80mL / min, the back pressure value of the back pressure valve to 2MPa, and the reaction residence time to 15s. The gas-liquid mixture flowed out from the outlet of the microreactor, first cooled to room temperature through the condenser, then passed through the back pressure valve and gas-liquid separator, the gas was discharged from the C port, and the liquid flowed out through the D port into the freeze dryer for collection and freeze drying, and finally a white solid product was obtained. The purity was 89.2% and the yield was 78.1%.

[0083] Table 1 summarizes the yield and purity data of each embodiment and comparative example, as follows:

[0084] Table 1 Statistics of experimental results of various embodiments and comparative examples

[0085]

[0086] The above detailed description is a specific description of one feasible embodiment of the present invention. The embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not deviate from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A method for preparing fondaparinux sodium pentasaccharide intermediate compound 1 using a continuous flow microreactor, characterized in that: The method comprises the following steps: dissolving compound 2 in a solvent to obtain a homogeneous solution; pumping the homogeneous solution into a microreactor in a continuous flow microreactor under a hydrogen atmosphere, contacting with a catalyst loaded in the microreactor to react; after the reaction is completed, lyophilizing the obtained reaction solution to obtain fondaparinux sodium pentasaccharide intermediate compound 1; the fondaparinux sodium pentasaccharide intermediate compound 1 and compound 2 have the following structural formulas: In the formula, R1, R2, R3, R4, R5 and R6 are independently selected from phenyl and substituted phenyl.

2. The method according to claim 1, characterized in that: The solvent is water or a mixed solvent consisting of water and an organic solvent; the substituted phenyl group includes a halogenated phenyl group.

3. The method according to claim 2, characterized in that The organic solvent is one or a combination of ethanol, propylene glycol, n-butanol, isopropanol, tert-butanol, polyethylene glycol, and dimethyl sulfoxide.

4. The method according to claim 1, characterized in that The homogeneous solution was pumped in at a flow rate of 1-60 mL / min.

5. The method according to claim 4, characterized in that The homogeneous solution was pumped in at a flow rate of 10-40 mL / min.

6. The method according to claim 1, characterized in that The catalyst is one or a mixture of activated carbon-supported palladium, alumina-supported palladium, polysilane-supported palladium and activated carbon-supported palladium hydroxide; the mass ratio of the catalyst to compound 2 is 0.46-2.33:

1.

7. The method according to claim 1, characterized in that The reaction temperature is 50-80° C., and the reaction time is 10-30 s.

8. The method according to claim 1, characterized in that After the reaction is completed, condensation is performed, and then gas-liquid separation is performed at a pressure of 0.1-5 MPa to obtain a reaction liquid.

9. The method according to claim 1, characterized in that: The microreactor is a fixed bed microreactor or a honeycomb microreactor.

10. The method according to claim 1, characterized in that The continuous flow microreactor comprises a liquid storage tank, a hydrogen source, a fully automatic micro-reaction hydrogenation system and a freeze dryer. The liquid storage tank is connected to the A port of the fully automatic micro-reaction hydrogenation system, the hydrogen source is connected to the B port of the fully automatic micro-reaction hydrogenation system, the freeze dryer is connected to the D port of the fully automatic micro-reaction hydrogenation system, and the fully automatic micro-reaction hydrogenation system comprises a microreactor.

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