Synthesis method of fondaparinux sodium intermediate D5
Starting from α-D-glucose pentaacetate, a multi-step reaction is carried out to synthesize the intermediate D5 of the fudalis sodium dichloride, which solves the problem of difficulty in obtaining raw materials and complex operation, and achieves high purity and high yield intermediate production, which is suitable for large-scale industrial production.
Patent Information
- Application Number
- CN202510109803.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-23
- Publication Date
- 2025-05-27
AI Technical Summary
In the prior art, the raw materials for the intermediate D5 of Fondalis sodium are difficult to obtain, the price is high, and the operation steps are complicated, which leads to difficulty in purification of intermediates, low yield and poor quality, affecting the quality of subsequent products.
Starting from the easily obtained raw material α-D-glucose pentaacetate, intermediate D5 is gradually synthesized through eight steps, including bromination, elimination, hydrolysis, cyclic iodo, azide substitution, benzyl substitution, Lewis-acetic anhydride ring opening and hydrazine acetate selective ester dissolution.
The high purity (greater than 99%) and high yield of intermediate D5 is achieved, which simplifies operating steps, reduces production costs, and is suitable for large-scale production.
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Figure CN120040523A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of pharmaceutical synthesis, and particularly to a method for synthesizing the intermediate D5 of fondaparinux sodium. Background Art
[0002] Fondaparinux sodium is a new type of antithrombotic drug. After heparin and low molecular weight heparin, it has been approved by the FDA for the treatment and prevention of various arteriovenous thrombosis. Fondaparinux sodium is used in patients undergoing major orthopedic surgeries of the lower extremities such as hip fractures, major knee surgeries, or hip replacement surgeries to prevent the occurrence of venous thromboembolism events and plays an important role in various biological processes such as blood coagulation, viral infection, inflammation, growth factor regulation, cell adhesion, cell growth, tumor metastasis, lipid metabolism, and nervous system diseases. The structure of fondaparinux sodium is as follows:
[0003]
[0004] D5 is an important pharmaceutical intermediate for synthesizing fondaparinux sodium. The structure of intermediate D5 is as follows: When preparing intermediate D5, there are more or less some problems in the prior art. For example: (1) The raw materials are not easily obtained and the price is relatively high, increasing the cost of industrial production; (2) The operation steps are complex and not easy to implement, which is not conducive to large-scale industrial application; (3) There are defects such as difficult purification of the intermediate, low yield, and poor quality. The quality and yield of intermediate D5 will affect the quality and yield of subsequent fondaparinux sodium intermediates, and even affect the quality and yield of the final product fondaparinux sodium. Therefore, it is necessary to develop a synthesis method for intermediate D5. Summary of the Invention
[0005] In view of the above-mentioned disadvantages of the prior art, the purpose of the present invention is to provide a method for synthesizing the intermediate D5 of fondaparinux sodium, which is used to solve the problems that the raw materials for producing intermediate D5 in the prior art are not easily obtained, and the yield and purity of intermediate D5 are relatively poor.
[0006] To achieve the above object and other related objects, a method for synthesizing the intermediate D5 of fondaparinux sodium is provided, including the following synthesis route:
[0007]
[0008] Specifically, it includes the following reaction steps:
[0009] Step 1: Using α-D-glucose pentaacetate as the starting material D0, reacting with a brominating reagent to undergo a bromination reaction to form compound D1;
[0010] Step 2: Compound D1 undergoes an elimination reaction to obtain compound D2;
[0011] Step 3: Compound D2 is hydrolyzed to obtain compound D3;
[0012] Step 4: Compound D3 undergoes a ring - closing iodination reaction with tetrabutyltin oxide and iodine to form compound D4;
[0013] Step 5: Compound D4 undergoes an azide substitution reaction to form compound D6;
[0014] Step 6: Compound D6 undergoes a benzyl substitution reaction to form compound D7;
[0015] Step 7: Compound D7 undergoes a ring - opening esterification reaction under the action of acetic anhydride and a Lewis acid to form compound D8;
[0016] Step 8: Compound D8 undergoes a hydrolysis reaction with acetic hydrazide to obtain the target product fondaparinux sodium intermediate D5.
[0017] Preferably, in Step 1, the bromination reagent is hydrobromic acid acetic acid solution; the temperature of the bromination reaction is in the range of 0 °C to 20 °C; the reaction solvent is dichloromethane (DCM); the reaction time is in the range of 8 h to 12 h.
[0018] More preferably, the concentration of hydrobromic acid in the hydrobromic acid acetic acid solution is in the range of 20% to 40%; preferably about 30%.
[0019] More preferably, after the bromination reaction, the organic phase is extracted, and after the organic phase is concentrated under reduced pressure, it is slurried with methyl tert - butyl ether and petroleum ether, filtered to obtain compound D1. The volume ratio of methyl tert - butyl ether to petroleum ether is 2:1.
[0020] Preferably, in Step 2, the excipients in the elimination reaction include zinc powder, acetic acid and copper acetate; the reaction solvent is sodium hydroxide aqueous solution; the temperature of the elimination reaction is about 5 °C to 15 °C, preferably 10 °C; the reaction time is in the range of 8 h to 12 h.
[0021] More preferably, after the elimination reaction, compound D2 is extracted with ethyl acetate.
[0022] Preferably, in Step 3, the excipients in the hydrolysis reaction include sodium methoxide and methanol; the temperature of the hydrolysis reaction is at room temperature; the reaction time of the hydrolysis reaction is in the range of 10 h to 14 h.
[0023] Preferably, in Step 4, the solvent for the ring - closing iodination reaction is acetonitrile (ACN); the reaction temperature is reflux and room temperature; molecular sieves are added during the reaction to provide an adsorption effect and promote the reaction; after the reaction, the intermediate D4 is obtained through extraction and purification.
[0024] More preferably, in step 4, compound D3, tin(IV) oxide bis(tributyltin) and acetonitrile are heated under reflux for 6 h under nitrogen protection. After cooling to below 10 °C, iodine is added, and the mixture is stirred at room temperature for 12 h. After extraction and trituration, intermediate D4 is obtained.
[0025] Preferably, in step 5, the auxiliary material for the azide substitution reaction is sodium azide; the reaction solvent is DMF; the reaction temperature is 110 °C to 130 °C, preferably 120 °C; the reaction time is 4 h to 8 h.
[0026] Preferably, in step 6, the auxiliary materials for the benzyl substitution reaction are benzyl bromide and sodium hydride; the reaction solvent is DMF; the reaction temperature is 5 °C to 20 °C, preferably 10 °C; the reaction time is 4 h to 8 h.
[0027] Preferably, in step 7, the Lewis acid is boron trifluoride diethyl etherate; the reaction temperature is 10 °C; the reaction time is 4 h to 6 h.
[0028] Preferably, in step 8, the reaction solvent for the hydrolysis reaction is DMF; the reaction temperature is 20 °C, and the reaction time is 4 h to 6 h.
[0029] Preferably, the specific synthesis route of the above synthesis method is as follows:
[0030]
[0031] As described above, the synthesis method of the fondaparinux sodium intermediate D5 of the present invention has the following beneficial effects: Starting from the easily obtainable raw material α-D-glucose pentaacetate, the intermediate D5 is successively obtained through bromination, elimination, hydrolysis, cyclization iodination, azide substitution, benzyl substitution, Lewis-acetic anhydride ring opening, and selective esterolysis with hydrazine acetate. The raw materials used in each step are simple and easily obtainable, the operation is simple, and it is easy to industrialize the production; and the yield of each step is relatively high, and the purity (greater than 99%) and yield of the final product intermediate D5 are also ideal, which is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS
[0032] Figure 1 It is the NMR spectrum of compound D2 prepared in Example 2 of the present invention.
[0033] Figure 2 It is the NMR spectrum of compound D3 prepared in Example 3 of the present invention.
[0034] Figure 3 It is the NMR spectrum of compound D4 prepared in Example 4 of the present invention.
[0035] Figure 4 It is the NMR spectrum of compound D6 prepared in Example 5 of the present invention.
[0036] Figure 5 This is the NMR spectrum of compound D7 prepared in Example 6 of the present invention.
[0037] Figure 6 This is the NMR spectrum of compound D8 prepared in Example 7 of the present invention.
[0038] Figure 7 This is the NMR spectrum of compound D5 prepared in Example 8 of the present invention.
[0039] Figure 8 This is the liquid chromatogram of compound D5 prepared in Example 8 of the present invention. Detailed implementation mode
[0040] The following specific examples illustrate the implementation modes of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification.
[0041] Example 1
[0042] Step 1:
[0043] Add 1 kg of α-D-glucose pentaacetate and 1 L of dichloromethane to a 3 L reaction flask, stir to dissolve and cool to 0 °C in an ice bath. Add 900 g of a 33% hydrobromic acid acetic acid solution, and stir and react at 10 °C - 20 °C for 10 h. Monitor the reaction of the raw materials by TLC until the reaction is complete; then add 1 kg of water, separate the layers, extract the aqueous phase with 500 mL of dichloromethane, combine the organic phases, wash with an aqueous sodium bicarbonate solution until neutral, concentrate the organic phase under reduced pressure, and slurry the obtained residue with 2 L of methyl tert-butyl ether and 1 L of petroleum ether for 2 h. Filter to obtain 950 g of compound D1 with a yield of 95%. The stability of D1 is poor, and it needs to be kept at a lower temperature and enter the next step of the reaction as soon as possible.
[0044] Example 2
[0045] Step 2:
[0046] Add 3 L of water and 300 g of NaOH to a 20 L reaction flask, stir to dissolve, and add 900 g of acetic acid, 40 g of copper acetate, and 600 g of zinc powder. Stir evenly and then lower the temperature to 10 °C; then dropwise add 1 L of an acetic acid solution containing 1 kg of compound D1. After the addition is complete, react for 10 h and monitor the reaction of the raw materials by TLC until the reaction is complete; after the reaction is over, add 2 L of ethyl acetate, filter and separate the layers, extract the aqueous phase with 1 L of ethyl acetate, combine the organic phases, wash with an aqueous sodium bicarbonate solution until neutral, and concentrate the organic phase under reduced pressure to obtain a residue of 0.63 kg, which is compound D2 with a yield of 95%. This product does not require further purification and directly enters the next step.
[0047] The NMR spectrum of compound D2 is as attached Figure 1as shown
[0048] Example 3
[0049] Step 3:
[0050] Add 1 Kg of Compound D2, 4 L of methanol and 40 g of a 33% sodium methoxide methanol solution to a 10 L reaction flask, react at room temperature for 12 h, monitor the reaction of the raw materials by TLC until completion, concentrate under reduced pressure to obtain 500 g of Compound D3 with a yield of 95%. This product does not require further purification and directly enters the next step.
[0051] The NMR spectrum of Compound D3 is as attached Figure 2 as shown
[0052] Example 4
[0053] Step 4:
[0054] Add 500 g of Compound D3, 3 L of acetonitrile, 500 g of dry 4A molecular sieve and 2 kg of tetrabutyltin oxide to a 10 L reaction flask, heat under reflux for 6 h under nitrogen protection, cool to below 10 °C, add 1 kg of iodine in batches, stir at room temperature for 12 h and then filter, distill off acetonitrile under reduced pressure; add 4 L of petroleum ether and 2 L of water, stir and separate the layers, collect the aqueous phase, and extract again with 2 L of petroleum ether to collect the aqueous phase. The aqueous phase is extracted 4 times with 2 L of ethyl acetate, the organic phases are combined, concentrated under reduced pressure to dryness, triturated with 500 mL of methyl tert-butyl ether and then filtered to obtain 600 g of Compound D4 with a yield of 65%.
[0055] The NMR spectrum of Compound D4 is as attached Figure 3 as shown
[0056] Example 5
[0057] Step 5:
[0058] Add 600 g of Compound D4, 600 g of sodium azide and 3 L of DMF to a 5 L reaction flask, heat to 120 °C under nitrogen protection and react for 6 h. After the reaction is completed, cool to room temperature and filter to obtain the DMF solution of Compound D6. This solution does not require further purification and enters the next step.
[0059] The NMR spectrum of Compound D6 is as attached Figure 4 as shown
[0060] Example 6
[0061] Step 6:
[0062] Add the DMF solution of compound D6 prepared in Example 5 to a 10 L reaction flask, then add 1.1 kg of benzyl bromide and 2 L of DMF. Cool the mixture to below 10 °C under nitrogen protection, and add 350 g of sodium hydride in batches. After the addition, stir the reaction mixture at room temperature for 6 h. Pour the reaction solution into 5 L of ice water, extract it 3 times with 3 L of methyl tert-butyl ether, combine the organic phases, and concentrate them under reduced pressure by rotary evaporation. The resulting residue is purified by column chromatography using PE / EA = 4 / 1 and recrystallized with 3 L of PE / EA = 2 / 1 to obtain 360 g of compound D7 with a purity of 98% and a two-step yield of 45%.
[0063] The NMR spectrum of compound D7 is shown in the appendix Figure 5 as follows.
[0064] Example 7
[0065] Step 7:
[0066] Add 350 g of compound D7 and 2 L of DCM to a 5 L reaction flask, cool it to 10 °C, and dropwise add 350 g of acetic anhydride and 12 g of boron trifluoride diethyl ether complex solution. After the addition, react at 10 °C for 5 h. When HPLC shows that compound D7 has reacted completely, pour the reaction solution into 3 L of ice water, separate the layers, extract with 2 L of DCM, combine the organic phases, concentrate them under reduced pressure by rotary evaporation, and then recrystallize with 3.5 L of PE / EA = 3 / 5 to obtain 335 g of compound D8 with a purity of 98% and a yield of 75%.
[0067] The NMR spectrum of compound D8 is shown in the appendix Figure 6 as follows.
[0068] Example 8
[0069] Step 8:
[0070] Add 300 g of compound D8 and 1.5 L of DMF to a 5 L reaction flask, cool the reaction system to 10 °C, and add 30 g of acetic hydrazide in batches. After the addition, react at 20 °C for 5 h. When HPLC shows that compound D8 has reacted completely, pour the reaction solution into 5 L of ice water, filter the obtained crude product, and recrystallize it with PE / EA = 1 / 1 to obtain 200 g of compound D5 with a purity of 99.557% and a yield of 75%.
[0071] The NMR spectrum of compound D5 is shown in the appendix Figure 7 as follows; the liquid chromatogram of compound D5 is shown in the appendix Figure 8 as follows.
[0072] In summary, the present invention starts from the readily available raw material α-D-glucose pentaacetate, and successively obtains the fondaparinux sodium intermediate D5 through 8 steps including bromination reaction, elimination reaction, hydrolysis reaction, cyclization iodination reaction with tetrabutyltin oxide and iodine, azide substitution reaction, benzyl substitution reaction, Lewis-acetic anhydride ring-opening esterification reaction, and selective hydrolysis reaction with hydrazine acetate. The raw materials used in each step are simple and readily available, the operation is simple, and it is easy to carry out industrial production; moreover, the yield of each step is relatively high, and the purity (greater than 99%) and yield of the final product intermediate D5 are also ideal, which is suitable for large-scale production. Therefore, the present invention effectively overcomes various disadvantages in the prior art and has high industrial utilization value.
[0073] The above embodiments are only illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Any person familiar with this technology can modify or change the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or changes made by those with ordinary knowledge in the technical field without departing from the spirit and technical ideas disclosed by the present invention should still be covered by the claims of the present invention.
Claims
1. A method for synthesizing fondaparinux sodium intermediate D5, characterized in that: The following synthetic routes are included: Specifically include the following reaction steps: Step 1, using α-D-glucose pentaacetate as the starting material D0, undergoing a bromination reaction with a bromination reagent to generate a compound D1; Step 2, compound D1 undergoes elimination reaction to obtain compound D2; Step 3, compound D2 is subjected to hydrolysis reaction to obtain compound D3; Step 4, compound D3 undergoes a ring-closing iodination reaction with tetrabutyltin oxide and iodine to generate compound D4; Step 5, compound D4 undergoes an azide substitution reaction to generate compound D6; Step 6, compound D6 undergoes benzyl substitution reaction to generate compound D7; Step 7, compound D7 undergoes a ring-opening esterification reaction under the action of acetic anhydride and Lewis acid to generate compound D8; Step 8: Compound D8 undergoes a hydrolysis reaction with hydrazine acetate to obtain the target product, fondaparinux sodium intermediate D5.
2. The synthesis method according to claim 1, characterized in that In step 1, the bromination reagent is a hydrobromic acid-acetic acid solution; the concentration of hydrobromic acid in the hydrobromic acid-acetic acid solution is 20% to 40%.
3. The synthesis method according to claim 1, characterized in that In step 2, the auxiliary materials in the elimination reaction include zinc powder, acetic acid and copper acetate; the temperature of the elimination reaction is about 5° C. to 15° C.; and the reaction time is 8 h to 12 h.
4. The synthesis method according to claim 1, characterized in that In step 3, the auxiliary materials in the hydrolysis reaction include sodium methoxide and methanol; the temperature of the hydrolysis reaction is room temperature; and the reaction time of the hydrolysis reaction is 10 h to 14 h.
5. The synthesis method according to claim 1, characterized in that In step 4, the solvent for the ring-closing iodination reaction is acetonitrile; compound D3, tetrabutyltin oxide and acetonitrile are heated to reflux for reaction for 6 hours under nitrogen protection, and after cooling to below 10°C, iodine is added, and the reaction is stirred at room temperature for 12 hours. After extraction and pulping, the intermediate D4 is obtained.
6. The synthesis method according to claim 1, characterized in that In step 5, the auxiliary material of the azide substitution reaction is sodium azide; the reaction solvent is DMF; the reaction temperature is 110° C. to 130° C.; and the reaction time is 4 h to 8 h.
7. The synthesis method according to claim 1, characterized in that In step 6, the auxiliary materials of the benzyl substitution reaction are benzyl bromide and sodium hydride; the reaction solvent is DMF; the reaction temperature is 5° C. to 20° C.; and the reaction time is 4 h to 8 h.
8. The synthesis method according to claim 1, characterized in that In step 7, the Lewis acid is boron trifluoride etherate; the reaction temperature is 10° C.; and the reaction time is 4 h to 6 h.
9. The synthesis method according to claim 1, characterized in that In step 8, the reaction solvent of the hydrolysis reaction is DMF; the reaction temperature is 20° C., and the reaction time is 4 h to 6 h.
10. The synthesis method according to any one of claims 1 to 9, characterized in that: The specific synthetic route of fondaparinux sodium intermediate D5 is as follows: