Method for preparing fondaparinux sodium by using continuous flow micro-reaction technology

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing fondaparinux sodium by using a continuous flow micro-reaction technology. Comprising the following steps: taking a compound shown as a formula (A) as a raw material, and performing sulfonation reaction, according to the method for preparing the fondaparinux sodium by utilizing the continuous flow micro-reaction technology, the obtaining cost of the fondaparinux sodium can be obviously reduced; by controlling the residence time, the reaction temperature and the feeding amount of the reaction, overhigh local temperature or overhigh concentration of the reaction system is avoided, the product quality is ensured, and the method has very important significance on large-scale production and application.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing fondaparinux sodium by utilizing continuous flow micro-reaction technology. Background Art

[0002] Fondaparinux sodium is a pure chemically synthesized heparin pentasaccharide anticoagulant developed by Sanofi, France. It is currently available in many countries including France, the United Kingdom, Germany, the United States and China. 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 is the first new type of highly selective factor Xa inhibitor, which can reversibly bind to antithrombin (AT), increasing the activity of AT inhibitor Xa by hundreds of times, thereby effectively inhibiting the coagulation cascade reaction. With a bioavailability of 100% and a half-life of more than 17 hours, it is the preferred pillar product among heparin products. Fondaparinux has a complex structure, a long synthesis route, high synthesis difficulty, and high production cost.

[0005] At present, the literature reporting the synthesis method of fondaparinux sodium includes US4818816, AU2008200567A1, US2012 / 0083594A1, US2013 / 0005954, CN103122012B, etc., and the disclosed method produces more impurities, resulting in a lower product yield, and the purification difficulty is extremely large, thereby making the obtained product purity not high. The methods disclosed in the existing documents are all intermittent production methods carried out in traditional reactors, and this production method itself has many insurmountable shortcomings, such as low production efficiency, unstable product quality, etc.

[0006] Continuous flow micro-reaction technology mainly utilizes microchannel reactors to enhance factors that affect organic synthesis reactions, such as mass transfer and heat transfer effects. By designing the flow pattern and mixing procedures of the substrate, the process parameters are controlled to improve the selectivity and rate of the reaction and enhance operational safety. Summary of the invention

[0007] In view of the shortcomings of the prior art, the present invention provides a method for preparing fondaparinux sodium using continuous flow micro-reaction technology, which can prepare fondaparinux sodium with high yield and high purity.

[0008] In order to achieve the purpose of the present invention, the technical solution adopted is as follows:

[0009] A method for preparing fondaparinux sodium using continuous flow micro-reaction technology comprises the following steps:

[0010] The compound of formula (A) is used as a raw material, subjected to sulfonation reaction, and purified to obtain the product;

[0011]

[0012] Further, the following steps are included:

[0013] (1) preparing a compound of formula (A) and a first solvent to form a homogeneous material I, preparing a sulfonating agent and a second solvent to form a homogeneous material II, and preparing a 1 M phosphate solution as a material III;

[0014] (2) Mix material I, material II and material III, react and purify to obtain the product.

[0015] Preferably, the sulfonating agent is one or more of N-ethyldiisopropylamine sulfur trioxide complex, trimethylammonium sulfur trioxide complex, sulfur trioxide pyridine complex, and sulfur trioxide triethylamine complex.

[0016] Preferably, the first solvent and the second solvent are respectively selected from one or more of methanol, ethanol, water, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide.

[0017] Preferably, the first solvent and the second solvent are selected from one or more of methanol, water, N,N-dimethylformamide and dimethyl sulfoxide.

[0018] Preferably, the molar concentration of the compound of formula (A) in the material I is 0.020 to 0.210 mmol / ml, preferably 0.030 to 0.080 mmol / ml.

[0019] Preferably, the molar concentration of the sulfonating agent in the material II is 0.010 to 0.5 mmol / ml, preferably 0.024 to 0.63 mmol / ml.

[0020] Preferably, the phosphate is a mixture of one or more of potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, magnesium phosphate, and magnesium dihydrogen phosphate, preferably one or more of sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. The pH value of material III is 8-12, preferably 9-11.

[0021] Preferably, after mixing in step (2), the molar ratio of the compound of formula (A) to the sulfonating agent is 1:5 to 1:17, preferably 1:7 to 1:12.

[0022] Preferably, the material I, material II and material III in step (2) are added to the reactor and mixed at a flow rate of 1 ml / min to 27 ml / min, preferably 10 ml / min to 20 ml / min.

[0023] Preferably, in step (2), the flow rates of material I and material II are equal, and the flow rate of material III is 1.6 to 2.7 times, preferably 1.8 to 2.3 times, the flow rate of material I or material II.

[0024] Preferably, in step (2), the reaction temperature is 60 to 85°C, preferably 65 to 80°C, more preferably 70 to 75°C.

[0025] Preferably, in step (2), the reaction time is 2 to 18 min, preferably 7 to 12 min.

[0026] Preferably, the reaction in step (2) is carried out in a continuous flow microchannel reactor, which comprises a metering pump I, a metering pump II, a metering pump III, a mixing module and a reaction module; the material I, the material II and the material III enter the mixing module through the metering pump I, the metering pump II and the metering pump III respectively, and then flow into the reaction module together for reaction.

[0027] Preferably, metering pump I is controlled to make the flow rate of material I 7-18 ml / min; metering pump II is controlled to make the flow rate of material II 7-18 ml / min; metering pump III is controlled to make the flow rate of material III 14-40 ml / min.

[0028] Preferably, after the reaction in step (2) is completed, the feed solution is concentrated under reduced pressure, then loaded onto a Sephadex G-25 column, eluted with water, and dried to obtain the product.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] (1) The present invention provides a method for preparing fondaparinux sodium using continuous flow microreactor technology, which can significantly reduce the acquisition cost of fondaparinux sodium and is of great significance for its large-scale production and application.

[0031] (2) The present invention controls the reaction residence time, reaction temperature, and feed amount to avoid excessively high local temperature or excessive concentration in the reaction system, thereby ensuring product quality;

[0032] (3) The present invention further screens the sulfonating reagent to obtain fondaparinux sodium with higher purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is the microchannel reaction flow chart. DETAILED DESCRIPTION

[0034] The present invention will be further described below in conjunction with specific implementation modes.

[0035] In the following specific embodiments, compound (A) is a fondaparinux sodium pentasaccharide intermediate with a purity of 95%.

[0036]

[0037] Example 1

[0038] (1) Weigh 100 g of compound (A) and dissolve it in 500 ml of methanol and 500 ml of purified water to prepare a homogeneous material I (the molar concentration of compound (A) is 0.07 mmol / ml); weigh 100 g of sulfur trioxide pyridine complex and dissolve it in 500 ml of methanol and 500 ml of purified water to prepare a homogeneous material II (the molar concentration of sulfur trioxide pyridine complex is 0.63 mmol / ml); use sodium dihydrogen phosphate and sodium hydroxide to prepare 2000 ml of 1 M phosphate aqueous solution with a pH of 10.3 as material III.

[0039] (2) Material I enters the mixing module through metering pump I, and metering pump I is controlled to make the flow rate of material I 12 ml / min; material II enters the mixing module through metering pump II, and metering pump II is controlled to make the flow rate of material II 12 ml / min; material III enters the mixing module through metering pump III, and metering pump III is controlled to make the flow rate of material III 24 ml / min; then, materials I, II, and III flow into the reaction module together, react at 70°C, and the residence time is 6 min.

[0040] The feed liquid was collected at the outlet of the microchannel reactor, and the liquid phase (HPLC) purity was greater than 95%. The mixture was concentrated under reduced pressure, loaded onto a Sephadex G-25 column, eluted with purified water, and dried by spin drying to obtain 116.7 g of a solid product of fondaparinux sodium, with a yield of 96% and a liquid phase (HPLC) purity of greater than 99.0%.

[0041] Example 2

[0042] (1) Weigh 100 g of compound (A) and dissolve it in 1000 ml of purified water to prepare a homogeneous material I (the molar concentration of compound (A) is 0.07 mmol / ml); weigh 78 g of sulfur trioxide pyridine complex and dissolve it in 1000 ml of methanol to prepare a homogeneous material II (the molar concentration of sulfur trioxide pyridine complex is 0.49 mmol / ml); use sodium dihydrogen phosphate and sodium hydroxide to prepare 1600 ml of 1 M phosphate aqueous solution with a pH of 10.8 as material III.

[0043] (2) Material I enters the mixing module through metering pump I, and metering pump I is controlled to make the flow rate of material I 9 ml / min; material II enters the mixing module through metering pump II, and metering pump II is controlled to make the flow rate of material II 9 ml / min; material III enters the mixing module through metering pump III, and metering pump III is controlled to make the flow rate of material III 14.4 ml / min; then, materials I, II, and III flow into the reaction module together, react at 75°C, and the residence time is 8 min.

[0044] The feed liquid was collected at the outlet of the microchannel reactor, and the liquid phase (HPLC) purity was greater than 96%. The mixture was concentrated under reduced pressure, loaded onto a Sephadex G-25 column, eluted with purified water, and spin-dried to obtain 119.1 g of a solid product of fondaparinux sodium, with a yield of 98% and a liquid phase (HPLC) purity of greater than 99.5%.

[0045] Example 3

[0046] (1) 300 g of compound (A) was weighed and dissolved in 1750 ml of N,N-dimethylacetamide (DMAc) and 1750 ml of purified water to prepare a homogeneous material I (the molar concentration of compound (A) was 0.03 mmol / ml); 116.9 g of trimethylammonium sulfur trioxide complex was weighed and dissolved in 1750 ml of N,N-dimethylacetamide (DMAc) and 1750 ml of purified water to prepare a homogeneous material II (the molar concentration of sulfur trioxide pyridine complex was 0.24 mmol / ml); 7700 ml of 1 M phosphate aqueous solution with a pH of 9.6 was prepared using disodium hydrogen phosphate and sodium hydroxide as material III.

[0047] (2) Material I enters the mixing module through metering pump I, and metering pump I is controlled to make the flow rate of material I 7 ml / min; material II enters the mixing module through metering pump II, and metering pump II is controlled to make the flow rate of material II 7 ml / min; material III enters the mixing module through metering pump III, and metering pump III is controlled to make the flow rate of material III 15.4 ml / min; then, materials I, II, and III flow into the reaction module together, react at 68°C, and the residence time is 12 min.

[0048] The feed liquid was collected at the outlet of the microchannel reactor, and the liquid phase (HPLC) purity was greater than 95%. The mixture was concentrated under reduced pressure, loaded onto a Sephadex G-25 column, eluted with purified water, and dried by spin drying to obtain 346.4 g of a solid product of fondaparinux sodium, with a yield of 95% and a liquid phase (HPLC) purity of greater than 99.5%.

[0049] Example 4

[0050] (1) 300 g of compound (A) was weighed and dissolved in 1750 ml of N,N-dimethylacetamide (DMAc) and 1750 ml of purified water to prepare a homogeneous material I (the molar concentration of compound (A) was 0.03 mmol / ml); 175.4 g of trimethylammonium sulfur trioxide complex was weighed and dissolved in 1750 ml of N,N-dimethylacetamide (DMAc) and 1750 ml of purified water to prepare a homogeneous material II (the molar concentration of sulfur trioxide pyridine complex was 0.36 mmol / ml); 7700 ml of 1 M phosphate aqueous solution with a pH of 10.1 was prepared as material III using disodium hydrogen phosphate and sodium hydroxide.

[0051] (2) Material I enters the mixing module through metering pump I, and metering pump I is controlled to make the flow rate of material I 18 ml / min; material II enters the mixing module through metering pump II, and metering pump II is controlled to make the flow rate of material II 18 ml / min; material III enters the mixing module through metering pump III, and metering pump III is controlled to make the flow rate of material III 39.6 ml / min; then, materials I, II, and III flow into the reaction module together, react at 77°C, and the residence time is 10 min.

[0052] The feed liquid was collected at the outlet of the microchannel reactor, and the liquid phase (HPLC) purity was greater than 97%. The mixture was concentrated under reduced pressure, loaded onto a Sephadex G-25 column, eluted with purified water, and spin-dried to obtain 339.1 g of a solid product of fondaparinux sodium, with a yield of 93% and a liquid phase (HPLC) purity of greater than 99.9%.

[0053] Comparative Example 1

[0054] (1) Weigh 100 g of compound (A) and dissolve it in 500 ml of N,N-dimethylformamide and 500 ml of purified water to prepare a homogeneous material I (the molar concentration of compound (A) is 0.07 mmol / ml); weigh 211.7 g of sulfur trioxide pyridine complex and dissolve it in 500 ml of N,N-dimethylformamide and 500 ml of purified water to prepare a homogeneous material II (the molar concentration of sulfur trioxide pyridine complex is 1.33 mmol / ml); use sodium dihydrogen phosphate and sodium hydroxide to prepare 2000 ml of 1 M phosphate aqueous solution with a pH of 10.3 as material III.

[0055] (2) Under stirring, material I and material III are added to the reactor in sequence, and material II is slowly added at room temperature, and the reaction is stirred for 48 hours. The mixture is concentrated under reduced pressure, loaded onto a Sephadex G-25 column, eluted with purified water, and spin-dried to obtain 88.7 g of a solid product of fondaparinux sodium, with a yield of 73% and a liquid phase (HPLC) purity of more than 95%.

[0056] Comparative Example 2

[0057] The difference from Example 4 is that the reaction temperature is different, specifically the reaction temperature is 50°C

[0058] (1) 300 g of compound (A) was weighed and dissolved in 1750 ml of N,N-dimethylacetamide (DMAc) and 1750 ml of purified water to prepare a homogeneous material I (the molar concentration of compound (A) was 0.03 mmol / ml); 175.4 g of trimethylammonium sulfur trioxide complex was weighed and dissolved in 1750 ml of N,N-dimethylacetamide (DMAc) and 1750 ml of purified water to prepare a homogeneous material II (the molar concentration of sulfur trioxide pyridine complex was 0.36 mmol / ml); 7700 ml of 1 M phosphate aqueous solution with a pH of 10.1 was prepared as material III using disodium hydrogen phosphate and sodium hydroxide.

[0059] (2) Material I enters the mixing module through metering pump I, and metering pump I is controlled to make the flow rate of material I 18 ml / min; material II enters the mixing module through metering pump II, and metering pump II is controlled to make the flow rate of material I 18 ml / min; material III enters the mixing module through metering pump III, and metering pump III is controlled to make the flow rate of material III 39.6 ml / min; then, materials I, II, and III flow into the reaction module together, react at 50°C, and the residence time is 10 min.

[0060] The feed liquid was collected at the outlet of the microchannel reactor, and the liquid phase (HPLC) purity was 85%. The mixture was concentrated under reduced pressure, loaded onto a Sephadex G-25 column, eluted with purified water, and dried by spin drying to obtain 291.7 g of a solid product of fondaparinux sodium, with a yield of 80.2% and a liquid phase (HPLC) purity greater than 90%.

[0062] Table 1 Statistics of experimental results of embodiments and comparative examples

[0063] Experimental Group Yield (%) Product purity (%) Example 1 96 Greater than 99.0 Example 2 98 Greater than 99.5 Example 3 95 Greater than 99.5 Example 4 93 Greater than 99.9 Comparative Example 1 73 Greater than 95 Comparative Example 2 80 90.4

[0064] The continuous flow microchannel reactor has efficient mass transfer and heat transfer, can realize the refined regulation of material ratio and accurate control of reaction temperature, and under the reaction conditions of the present invention, reduces the occurrence of side reactions, so that the product yield and purity are greatly improved. As shown in Table 1, the present invention adopts continuous flow micro-reaction technology to prepare fondaparinux sodium under the reaction conditions of the present invention, which has obvious advantages.

[0065] 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 using continuous flow microreactor technology, characterized in that: The steps include: (1) Under the action of a solvent, the compound of formula (A) is prepared into a homogeneous material I, the sulfonating agent is prepared into a homogeneous material II; and a phosphate solution is prepared as a material III; (2) Mix material I, material II and material III to obtain; 2. The method according to claim 1, characterized in that The sulfonating agent is one or more of N-ethyldiisopropylamine sulfur trioxide complex, trimethylammonium sulfur trioxide complex, sulfur trioxide pyridine complex, and sulfur trioxide triethylamine complex.

3. The method according to claim 1, characterized in that: The solvent is selected from one or more of methanol, ethanol, water, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide.

4. The method according to claim 1, characterized in that: The molar concentration of the compound of formula (A) in the material I is 0.020-0.210 mmol / ml, preferably 0.030-0.080 mmol / ml.

5. The method according to claim 1, characterized in that The molar concentration of the sulfonating agent in the material II is 0.010 to 0.5 mmol / ml, preferably 0.024 to 0.63 mmol / ml.

6. The method according to claim 1, characterized in that The phosphate is a mixture of one or more of potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, magnesium phosphate, and magnesium dihydrogen phosphate, preferably one or more of sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. The concentration of the phosphate solution is 0.5-1.5M, and the pH value of the material III is 8-12, preferably 9-11.

7. The method according to claim 1, characterized in that In step (2), the molar ratio of the compound of formula (A) to the sulfonating agent is 1:5 to 1:17, preferably 1:7 to 1:

12.

8. The method according to claim 1, characterized in that In step (2), the reaction temperature is 60 to 85° C., preferably 65 to 80° C., more preferably 70 to 75° C.; and / or the reaction time is 2 to 18 min, preferably 7 to 12 min.

9. The method according to any one of claims 1 to 8, characterized in that: The reaction in step (1) and / or step (2) is carried out in a microchannel reactor, and the continuous flow microchannel reactor comprises a metering pump I, a metering pump II, a metering pump III, a mixing module and a reaction module; the material I, the material II and the material III enter the mixing module through the metering pump I, the metering pump II and the metering pump III respectively, and then flow into the reaction module together for reaction.

10. The method according to any one of claims 1 to 8, characterized in that: After the reaction in step (2) is completed, the feed solution is concentrated under reduced pressure, then loaded onto a Sephadex G-25 column, eluted with water, and dried to obtain the product.

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