Method for synthesizing cis-propenylphosphonic acid through continuous flow hydrogenation under catalysis of porous organic polymer supported palladium
By using a continuous flow hydrogenation method with a palladium catalyst supported on a porous organic polymer in a microreactor, the shortcomings of the batch hydrogenation method of propadiene phosphonic acid in the prior art have been overcome, and efficient and safe preparation of cis-propadiene phosphonic acid has been achieved, improving production efficiency and selectivity.
Patent Information
- Application Number
- CN202511370138.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-24
- Publication Date
- 2025-12-26
AI Technical Summary
In the existing technology, the batch reactor hydrogenation method of propadiene phosphonic acid has problems such as loss of precious metal catalyst, low reaction selectivity, poor production efficiency and high labor intensity, which makes it difficult to meet the requirements of efficient preparation of cispropene phosphonic acid, an intermediate of fosfomycin.
A continuous flow hydrogenation synthesis of cis-propylene phosphonic acid was carried out in a microreactor using a palladium catalyst supported on a porous organic polymer. By loading the palladium catalyst onto the porous organic polymer, the efficient mass and heat transfer characteristics of the microreactor were utilized to achieve simple separation of the catalyst and the product, thereby improving reaction selectivity and production efficiency.
It improves the selectivity of the hydrogenation reaction of propylene phosphonic acid, reduces the loss of precious metal catalysts, enhances the synthesis efficiency and safety of cis-propylene phosphonic acid, and reduces production costs.
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Figure CN121202913A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to a method for synthesizing cis-propenylphosphonic acid by palladium-catalyzed continuous flow hydrogenation supported on porous organic polymers. Background Technology
[0002] Fosfomycin is a broad-spectrum antibiotic, mainly available in sodium, calcium, and tromethamine salts. It exhibits good inhibitory activity against both Gram-positive and Gram-negative bacteria, is unlikely to cause sensitization or develop resistance, and is widely used.
[0003] cis-propenzymic acid (C3H7PO3) is an important intermediate in the synthesis of fosfomycin and is a pale yellow liquid at room temperature. Currently, industrial production mainly uses the direct catalytic hydrogenation of propadienephosphonic acid to produce cis-propenzymic acid, employing a Pd / C catalyst in a stirred reactor batch process. Due to the high activity of Pd / C, the activation energies for hydrogenation of the two double bonds in propadienephosphonic acid are not significantly different, resulting in low selectivity and a tendency for over-hydrogenation to produce propylphosphonic acid, along with byproducts such as allylphosphonic acid and trans-propenzymic acid. Feng Xiaoling et al. reported a new process for the selective hydrogenation of propadienephosphonic acid to cis-propenzymic acid catalyzed by a Lindlar catalyst, with better selectivity than the Pd / C catalyst (Feng Xiaoling et al., Journal of Zhejiang University of Technology, 2010, 38, 15-19). However, this catalyst contains lead, which is difficult to remove from the raw materials, making its application in the production of pharmaceutical intermediates challenging.
[0004] The direct catalytic hydrogenation of propylene phosphonic acid is a typical gas-liquid-solid three-phase catalytic reaction, with the reaction occurring on the catalyst surface. The batch-type hydrogenation method used in this process results in a slow reaction rate, and the physical loss of the catalyst due to mechanical stirring also leads to a decrease in catalyst performance. Furthermore, the difficulty in separating the catalyst and the reactant liquid inevitably leads to problems such as low production efficiency, high energy and material consumption, and high labor intensity. Micro-reaction continuous hydrogenation processes can provide a larger gas-liquid-solid interface contact area, enhance the gas-liquid-solid mass transfer process, improve catalyst utilization, significantly shorten the hydrogenation reaction time, improve reaction selectivity, and avoid the catalyst separation process, thus improving operational safety and simplicity. In recent years, it has received widespread attention in the field of pharmaceutical intermediate synthesis (CO Kappe et al., Angew. Chem. Int. Ed. 2015, 54, 6688).
[0005] Porous organic polymers are amorphous polymers widely cross-linked by covalent bonds, mainly composed of elements such as C, H, O, N, P, and S. They possess advantages such as large specific surface area, controllable pore size, and high chemical stability. They can effectively support transition metals to form heterogeneous catalysts, achieving efficient separation of catalysts and products. Simultaneously, mass transfer can be optimized by controlling pore size, enhancing catalytic activity and selectivity. Porous organic polymers have become ideal catalyst supports in continuous flow catalytic reactions and hold promise for large-scale production of pharmaceutical intermediates (Y. Miura et al., ChemPlusChem 2024, 89, e202400039).
[0006] In summary, the current batch hydrogenation method for preparing cis-propenylphosphonic acid, a crucial intermediate in the industrial production of fosfomycin, suffers from problems such as precious metal catalyst loss, low reaction selectivity, poor production efficiency, and high labor intensity, indicating significant room for improvement. This patent utilizes palladium supported on a porous organic polymer as a catalyst and employs a micro-reaction continuous hydrogenation method, aiming to improve the selectivity of the propenylphosphonic acid hydrogenation reaction, reduce precious metal catalyst loss, increase the synthesis efficiency of cis-propenylphosphonic acid, enhance the safety and simplicity of the preparation process, and reduce the production cost of fosfomycin. Summary of the Invention
[0007] To address the above problems, this invention provides a method for preparing cis-propylene phosphonic acid by continuous flow hydrogenation supported on a porous organic polymer using palladium catalysis.
[0008] The present invention adopts the following technical solution: A method for synthesizing cis-propenylphosphonic acid by continuous flow hydrogenation catalyzed by palladium supported on a porous organic polymer is disclosed. The method uses propylene phosphonic acid as a raw material, which is dissolved in a solvent and then continuously catalytically hydrogenated in a micro-packed bed reactor containing a palladium catalyst supported on a porous organic polymer at a certain temperature and pressure to prepare cis-propenylphosphonic acid.
[0009] Furthermore, the structure of the porous organic polymer-supported palladium catalyst is as follows:
[0010] Furthermore, the solvent is one or a mixture of toluene, cyclohexane, and tetrahydrofuran.
[0011] Furthermore, the reaction temperature is 10~70°C and the hydrogen pressure is 0.1~0.5MPa.
[0012] Furthermore, the preparation method of the porous organic polymer-supported palladium catalyst includes: S1: Anhydrous aluminum trichloride was added to a 1,2-dichloroethane solution of thiophene, tris(2-thienyl)phosphine and dimethylformaldehyde to obtain a reaction solution, which was then stirred. S2: Add methanol to the reaction solution and stir, then filter and wash with methanol. Transfer the solid to a Soxhlet extractor and extract with dichloromethane, chloroform and methanol under reflux. The obtained solid is dried under vacuum to obtain polymer A. S3: Add the methanol solution of Pd(OAc)2 dropwise to the methanol suspension of polymer A, stir to react, and obtain the reaction suspension; S4: After cooling the reaction suspension, add a methanol solution of NaBH4 dropwise and then heat and stir to react; S5: Filter the solid and wash it repeatedly with methanol, water and ethanol. After vacuum drying, a porous organic polymer supported palladium catalyst is obtained.
[0013] Furthermore, in step S1, the reaction solution is first stirred at a first temperature for a first duration, and then heated to a second temperature and stirred for a second duration; the second duration is longer than the first duration.
[0014] Furthermore, the first temperature is 45°C, and the second temperature is 80°C.
[0015] Furthermore, the first duration is 5 hours, and the second duration is 60 hours.
[0016] Further, in step S2, after the reaction solution cools to room temperature, methanol is added and stirred for 1 hour. The mixture is then filtered, washed with methanol, and the solid is transferred to a Soxhlet extractor. Under reflux, it is extracted with dichloromethane, chloroform, and methanol for 12 hours each. The resulting solid is then vacuum dried at 60°C for 12 hours to obtain polymer A.
[0017] Furthermore, in step S3, a methanol solution of Pd(OAc)2 is added dropwise to a methanol suspension of polymer A at 25°C, and the mixture is stirred at 25°C for 24 hours.
[0018] Furthermore, in step S4, the reaction suspension is cooled to 0°C, a methanol solution of NaBH4 is added dropwise, and the temperature is raised to 25°C and the mixture is stirred for 24 hours.
[0019] Compared with existing processes, the present invention, by adopting the above process scheme, has the following advantages: 1. The continuous hydrogenation reaction of propylene phosphonic acid of the present invention is carried out in a micro-packed bed reactor. The reaction liquid enters the reactor in a plug flow manner, which has high mass and heat transfer efficiency, short reaction time and high reaction selectivity.
[0020] 2. This invention is applied to the preparation of cis-propylene phosphonic acid, which is highly safe, enables simple separation of catalyst and product, reduces physical loss of catalyst, reduces labor intensity, and enhances product competitiveness.
[0021] The present invention will now be described in detail with reference to the accompanying drawings and embodiments. Attached Figure Description
[0022] Figure 1 This is a schematic diagram of the reaction process of a porous organic polymer supported on a palladium catalyst according to an embodiment of the present invention; Figure 2 The NMR spectrum of the crude product prepared in Example 2 of this invention is shown. Figure 3 The image shows the phosphine NMR spectrum of the crude product prepared in Comparative Example 1 of this invention. Detailed Implementation
[0023] The principles and features of the present invention are described below with reference to the accompanying drawings. The examples given are only for explaining the present invention and are not intended to limit the scope of the present invention.
[0024] Example 1:
[0025] Preparation of palladium catalyst supported on porous organic polymer: Anhydrous aluminum trichloride (4.87 g, 30 mmol) was added to a solution of thiophene (0.85 g, 10 mmol), tris(2-thienyl)phosphine (2.80 g, 10 mmol), and dimethylformaldehyde (2.29 g, 30 mmol) in 50 mL of 1,2-dichloroethane. The reaction mixture was stirred at 45°C for 5 hours, then heated to 80°C and stirred for 60 hours. After cooling to room temperature, 50 mL of methanol was added and stirred for one hour. The mixture was filtered, washed with methanol, and the solid was transferred to a Soxhlet extractor. Extraction was performed under reflux with dichloromethane, chloroform, and methanol for 12 hours, respectively. The resulting solid was dried under vacuum at 60°C for 12 hours to obtain polymer A. A 50 mL methanol solution of Pd(OAc)₂ (2.25 g) was added dropwise to a 300 mL methanol suspension of polymer A at 25°C, and the mixture was stirred at 25°C for 24 hours. The reaction suspension was then cooled to 0°C, and a 20 mL (1.0 M) methanol solution of NaBH₄ was added dropwise. The mixture was then heated to 25°C and stirred for 24 hours. After filtration, the resulting solid was washed repeatedly with methanol, water, and ethanol, and dried under vacuum at 60°C for 12 hours to obtain a porous organic polymer-supported palladium catalyst.
[0026] Example 2: Combination Figure 1 A porous organic polymer-supported palladium catalyst was packed into a stainless steel micro-packed bed reactor with an inner diameter of 5 mm and a length of 50 mm. The reactor was placed in a constant temperature water bath, and the system was purged with nitrogen for 3 minutes. Under the conditions of temperature 25°C, hydrogen flow rate of 20 mL / min, liquid flow rate of 0.2 mL / min, and pressure of 0.1 MPa, a 10 wt.% tetrahydrofuran solution of propadiene phosphonate was introduced. The reaction conversion rate was 98.5% and the reaction selectivity was 87%. Figure 2The image shows the phosphine NMR spectrum of the crude product prepared in Example 2 of this invention.
[0027] Example 3: Combination Figure 1 A porous organic polymer-supported palladium catalyst was loaded into a stainless steel micro-packed bed reactor with an inner diameter of 5 mm and a length of 50 mm. The reactor was placed in a constant temperature water bath, and the system was purged with nitrogen for 3 minutes. Under the conditions of temperature 25°C, hydrogen flow rate of 20 mL / min, liquid flow rate of 0.2 mL / min, and pressure of 0.3 MPa, a 10 wt.% tetrahydrofuran solution of propadiene phosphonate was introduced. The reaction conversion rate was >99% and the reaction selectivity was 84%.
[0028] Example 4: Combination Figure 1 A porous organic polymer-supported palladium catalyst was loaded into a stainless steel micro-packed bed reactor with an inner diameter of 5 mm and a length of 50 mm. The reactor was placed in a constant temperature water bath, and the system was purged with nitrogen for 3 minutes. Under the conditions of temperature 45°C, hydrogen flow rate of 20 mL / min, liquid flow rate of 0.2 mL / min, and pressure of 0.1 MPa, a 10 wt.% tetrahydrofuran solution of propadiene phosphonate was introduced. The reaction conversion rate was >99% and the reaction selectivity was 84%.
[0029] Example 5: Combination Figure 1 A porous organic polymer-supported palladium catalyst was loaded into a stainless steel micro-packed bed reactor with an inner diameter of 5 mm and a length of 50 mm. The reactor was placed in a constant temperature water bath, and the system was purged with nitrogen for 3 minutes. Under the conditions of temperature 25°C, hydrogen flow rate of 20 mL / min, liquid flow rate of 0.2 mL / min, and pressure of 0.1 MPa, a 10 wt.% tetrahydrofuran-toluene mixed solution of propadienephosphonate was introduced. The reaction conversion rate was 94% and the reaction selectivity was 88%.
[0030] Comparative Example 1: Add 15g of 20wt.% propadiene phosphonic acid ethanol solution and 0.15g of 5% Pd / C catalyst to a 50mL autoclave. Purge with nitrogen three times, then purge with hydrogen to 0.1MPa. React at 25°C until the system pressure no longer changes. The reaction conversion rate is >99% and the reaction selectivity is 72%. Figure 3 The image shows the phosphine NMR spectrum of the crude product prepared in Comparative Example 1 of this invention.
[0031] The above description provides examples of the preferred embodiments of the present invention. Parts not detailed herein are common knowledge to those skilled in the art. The scope of protection of the present invention is determined by the claims. Any equivalent modifications based on the technical teachings of the present invention are also within the scope of protection of the present invention.
Claims
1. A method for synthesizing cis-propylenephosphonic acid via palladium-catalyzed continuous flow hydrogenation supported on a porous organic polymer, characterized in that, Cis-propenzymatic acid was prepared by continuous catalytic hydrogenation of propylene phosphonic acid in a micro-packed bed reactor containing a porous organic polymer-supported palladium catalyst at 10–70°C and a hydrogen pressure of 0.1–0.5 MPa, after being dissolved in a solvent.
2. The method for synthesizing cis-propylenephosphonic acid by palladium-catalyzed continuous flow hydrogenation of porous organic polymers according to claim 1, characterized in that, The structure of the porous organic polymer-supported palladium catalyst is as follows: 。 3. The method for synthesizing cis-propylenephosphonic acid by palladium-catalyzed continuous flow hydrogenation supported on porous organic polymers according to claim 1, characterized in that, The solvent is one or a mixture of toluene, cyclohexane, and tetrahydrofuran.
4. The method for synthesizing cis-propylenephosphonic acid by palladium-catalyzed continuous flow hydrogenation supported on porous organic polymers according to claim 1, characterized in that, The preparation method of the porous organic polymer supported palladium catalyst includes: S1: Anhydrous aluminum trichloride was added to a 1,2-dichloroethane solution of thiophene, tris(2-thienyl)phosphine and dimethylformaldehyde to obtain a reaction solution, which was then stirred. S2: Add methanol to the reaction solution and stir, then filter and wash with methanol. Transfer the solid to a Soxhlet extractor and extract with dichloromethane, chloroform and methanol under reflux. The obtained solid is dried under vacuum to obtain polymer A. S3: Add the methanol solution of Pd(OAc)2 dropwise to the methanol suspension of polymer A, stir to react, and obtain the reaction suspension; S4: After cooling the reaction suspension, add a methanol solution of NaBH4 dropwise and then heat and stir to react; S5: Filter the solid and wash it repeatedly with methanol, water and ethanol. After vacuum drying, a porous organic polymer supported palladium catalyst is obtained.
5. The method for synthesizing cis-propylenephosphonic acid by palladium-catalyzed continuous flow hydrogenation supported on porous organic polymers according to claim 4, characterized in that, In step S1, the reaction solution is first stirred at a first temperature for a first duration, and then heated to a second temperature and stirred for a second duration; the second duration is longer than the first duration.
6. The method for synthesizing cis-propylenephosphonic acid by palladium-catalyzed continuous flow hydrogenation supported on porous organic polymers according to claim 5, characterized in that, The first temperature is 45°C, and the second temperature is 80°C.
7. The method for synthesizing cis-propylenephosphonic acid by palladium-catalyzed continuous flow hydrogenation supported on porous organic polymers according to claim 5, characterized in that, The first duration is 5 hours, and the second duration is 60 hours.
8. The method for synthesizing cis-propylenephosphonic acid by palladium-catalyzed continuous flow hydrogenation supported on porous organic polymers according to claim 4, characterized in that, In step S2, after the reaction solution is cooled to room temperature, methanol is added to the reaction solution and stirred for 1 hour. After filtration and washing with methanol, the solid is transferred to a Soxhlet extractor and extracted with dichloromethane, chloroform and methanol under reflux for 12 hours respectively. The obtained solid is dried under vacuum at 60°C for 12 hours to obtain polymer A.
9. The method for synthesizing cis-propylenephosphonic acid by palladium-catalyzed continuous flow hydrogenation supported on porous organic polymers according to claim 4, characterized in that, In step S3, a methanol solution of Pd(OAc)2 is added dropwise to a methanol suspension of polymer A at 25°C, and the mixture is stirred at 25°C for 24 hours.
10. The method for synthesizing cis-propylenephosphonic acid by palladium-catalyzed continuous flow hydrogenation supported on porous organic polymers according to claim 4, characterized in that, In step S4, the reaction suspension is cooled to 0°C, a methanol solution of NaBH4 is added dropwise, and the temperature is raised to 25°C and the mixture is stirred for 24 hours.