Method for continuously synthesizing 1-hydroxybutyl diethyl phosphonate
The reaction between diethyl phosphite and n-butyraldehyde in a micro reactor through continuous catalytic synthesis method is solved, and the problems of long reaction cycle and low efficiency in the prior art are achieved, and a high yield, safe and efficient 1-hydroxybutyron is achieved Production of diethyl phosphonate.
Patent Information
- Application Number
- CN202411278829.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-12
- Publication Date
- 2024-12-17
AI Technical Summary
The existing synthesis technology of diethyl 1-hydroxybutylphosphonate has problems such as long reaction cycle, low production efficiency, high processing cost, cumbersome operation risk and low automation.
The continuous catalytic synthesis method is adopted to conduct micro-mix reactions of diethyl phosphite and n-butyraldehyde in a tetrahydrofuran solvent, and conduct continuous contact and reaction through a micro reactor to control the reaction temperature and time, and improve the reaction efficiency and safety.
The reaction cycle is greatly shortened, the product yield is improved to more than 95%, the process operation is simplified, and the safety and automation are improved.
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Figure CN119143799A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the field of chemical synthesis, and in particular to a method for continuously synthesizing diethyl 1-hydroxybutylphosphonate. Background Art
[0002] Phosphate ester prodrugs are a type of prodrug that uses a phosphate group as a carrier and is chemically connected to the hydroxyl group in the structure of the original drug to produce its phosphate monoester and its salt. They help to improve drug bioavailability, increase water solubility, increase drug stability, reduce toxic side effects, and promote long-term drug effectiveness.
[0003] At present, the method for industrial production of diethyl 1-hydroxybutylphosphonate is as follows:
[0004] Grinding method: Using diethyl phosphite and aromatic aldehyde as raw materials and triethylenediamine as catalyst, the reaction was ground in a mortar at room temperature for 15 minutes, and the yield of the product could reach 83.6% (Chemistry & Bioengineering, 2023, 40(7): 27-29, 33).
[0005] Triethylamine catalytic method: diethyl phosphite and hetero (aromatic) ring substituted aldehyde are used as raw materials, and triethylamine is used as catalyst. Heat to 60℃~80℃ in an oil bath and stir for 1.5h, then stir at room temperature overnight. Triethylamine is evaporated under reduced pressure, and the crude product is separated by silica gel column chromatography. The product yield is 91% (Chemical Reagents, 2008, 30(1):1-3).
[0006] Pudovik reaction method: Using diethyl phosphite as raw material, it reacts with aromatic aldehyde in the presence of catalyst triethylenediamine (DABCO) and solvent THF to undergo Pudovik reaction. The reaction system is stirred at room temperature for 2 hours and then concentrated under reduced pressure. The crude product is separated by silica gel column chromatography. The product yield is 81.4% to 91.5% (Chemical Engineer, 2022, 11(10): 1-2.).
[0007] The autoclave normal temperature solvent-free method: using diethyl phosphite as raw material, adding catalyst and aldehydes to react under solvent-free conditions, stirring at room temperature for 3 hours, the product yield is 68.23% (ROYAL SOCIETY OF CHEMISTRY, 2013, 43(10): 2521-2526).
[0008] The above-mentioned synthesis technology of 1-hydroxybutyl diethyl phosphonate has the problems of long reaction cycle, low production efficiency, high processing cost, dangerous and complicated operation, low degree of automation, etc. Summary of the invention
[0009] In order to overcome the problems existing in the current preparation process of 1-hydroxybutyl diethyl phosphonate, the present invention provides a method for continuously catalytically synthesizing 1-hydroxybutyl diethyl phosphonate, which can not only obtain a product with a higher yield, but also greatly shorten the reaction cycle of 1-hydroxybutyl diethyl phosphonate, and the process operation is simple, the process is easy to control, and the safety is high.
[0010] The specific steps of the present invention are as follows:
[0011] 1) dissolving diethyl phosphite and potassium tert-butoxide in tetrahydrofuran solution to prepare a first feed liquid; dissolving n-butyraldehyde in tetrahydrofuran solution to prepare a second feed liquid;
[0012] 2) continuously pumping the first feed liquid and the second feed liquid into a micro mixer for full contact and mixing to obtain a mixed material;
[0013] 3) The mixed material is transported to the reaction coil and maintained at the reaction temperature to react to obtain a liquid containing a reaction product; wherein the reaction equation is as shown in Formula I:
[0014]
[0015] As a preferred embodiment of the present invention, the molar ratio of diethyl phosphite to n-butyraldehyde in the mixed material of step 2) is 1:(1.5-3), more preferably 1:(1.8-2).
[0016] As a preferred embodiment of the present invention, the concentration range of diethyl phosphite in the first feed liquid is 0.002-0.01 mol / mL, more preferably 0.003-0.008 mol / mL. The concentration range of n-butyraldehyde in the second feed liquid is 0.003-0.03 mol / mL, more preferably 0.0054-0.016 mol / mL. The amount of potassium tert-butoxide in the first feed liquid is 5wt%-20wt% of the amount of diethyl phosphite, more preferably 10wt%-15wt%.
[0017] As a preferred embodiment of the present invention, in step 2), the flow rate of the first liquid is 4.0 to 8.0 mL / min, preferably 4.0 to 5.0 mL / min. The flow rate of the second liquid is 2.0 to 6.0 mL / min, preferably 2.0 to 4.0 mL / min. The reaction time of the material in the microreactor is 5 min to 15 min, preferably 8 min to 12 min. The reaction temperature is 50°C to 80°C, preferably 60°C to 70°C. The inner diameter of the reaction coil is 1.5 mm to 3 mm, preferably 2 mm. The dispersion scale of the micromixer is 250 to 750 μm, preferably 450 to 550 μm.
[0018] Compared with the prior art, the present invention has the following beneficial effects:
[0019] The present invention selects tetrahydrofuran as the solvent, which has a certain solvent effect and also has a promoting effect on the reaction;
[0020] The present invention continuously synthesizes 1-hydroxybutylphosphonic acid diethyl ester from a first feed liquid and a second feed liquid in a microreactor, and the synthesis reaction time is less than 20 minutes, thereby overcoming the problems in the prior art of 1) a long reaction period, which mostly requires a synthesis time of hours, 2) the reaction conditions in the reactor cannot be accurately controlled, such as the reaction temperature, the reaction time, etc., and 3) the problem of being unable to achieve continuous production and having low mixing efficiency.
[0021] The yield of 1-hydroxybutylphosphonic acid diethyl ester of the invention reaches more than 95%, and the conversion rate of diethyl phosphite, a main raw material, reaches more than 95%. BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Figure 1 The present invention is a process flow chart for the continuous synthesis of diethyl 1-hydroxybutylphosphonate. DETAILED DESCRIPTION
[0023] The present invention is further described and illustrated below in conjunction with specific embodiments. The embodiments are merely exemplary of the present disclosure and do not define the scope of limitation. The technical features of each embodiment of the present invention may be combined accordingly without conflicting with each other.
[0024] like Figure 1 As shown, the method of the present invention is used to continuously synthesize 1-hydroxybutylphosphonic acid diethyl ester, and the specific steps are as follows:
[0025] 1): using tetrahydrofuran as solvent, adding diethyl phosphite and potassium tert-butoxide to prepare a first feed solution, wherein the concentration of diethyl phosphite is in the range of 0.002 to 0.01 mol / mL, and the amount of potassium tert-butoxide is 5% to 20% of the amount of diethyl phosphite, and the solution is set aside;
[0026] 2) using tetrahydrofuran as solvent and adding n-butyraldehyde to prepare a second feed solution, wherein the concentration of n-butyraldehyde is in the range of 0.003 to 0.03 mol / mL solution, and setting aside;
[0027] 3) The first liquid and the second liquid prepared in advance are continuously delivered to the micro mixer through a horizontal flow pump, and a one-way valve is introduced to prevent backflow caused by unstable system pressure; wherein the flow rate of the first liquid is 4.0-8.0 mL / min; the flow rate of the second liquid is 2.0-6.0 mL / min; the temperature during mixing is 40° C.-80° C.;
[0028] 4) After the first liquid feed and the second liquid feed are mixed by a T-type micro mixer, the mixed material is input into a reaction coil for reaction, the reaction temperature is controlled at 50° C. to 80° C., and the reaction time is 5 min to 15 min; the reaction coil uses an oil bath to provide the reaction heat required during the reaction process;
[0029] 5) collecting the reaction liquid coming out of the pipeline to obtain a crude product of 1-hydroxybutylphosphonic acid diethyl ester, and using gas chromatography external standard quantitative analysis to analyze the content and purity of the target product in the product.
[0030] In the present invention, the reaction equation for synthesizing diethyl 1-hydroxybutylphosphonate is shown in Formula I:
[0031]
[0032] Embodiment 1:
[0033] The first feed liquid of 0.003 mol / mL diethyl phosphite and the second feed liquid of 0.008 mol / mL n-butyraldehyde were prepared with tetrahydrofuran as solvent. The amount of potassium tert-butoxide in the first feed liquid was 13% of the amount of diethyl phosphite. The first feed liquid and the second feed liquid were respectively transported to the micro mixer at a flow rate of 4.2 mL / min and 2.9 mL / min by a horizontal flow pump to start mixing. At this time, the molar ratio of diethyl phosphite to n-butyraldehyde in the mixed material was 1:1.84, and the dispersion scale of the micro mixer was 450 μm. After mixing, the reaction liquid entered the oil bath temperature control zone, the reaction coil temperature was controlled at 60°C, the inner diameter of the coil was 2 mm, the reaction residence time of the two streams of materials in the temperature control zone was 10.8 min, and the reaction product was collected at the outlet of the system. The collected samples were analyzed by gas chromatography and combined with the external standard curve to calculate that the yield of 1-hydroxybutyl phosphonic acid diethyl ester was 95.34%, and the conversion rate of diethyl phosphite was 96.30%.
[0034] Embodiment 2:
[0035] The first feed liquid of 0.008 mol / mL diethyl phosphite and the second feed liquid of 0.016 mol / mL n-butyraldehyde were prepared with tetrahydrofuran as solvent. The amount of potassium tert-butoxide in the first feed liquid was 15% of the amount of diethyl phosphite. The first feed liquid and the second feed liquid were respectively transported to the micro mixer at a flow rate of 4.0 mL / min and 4.0 mL / min by a horizontal flow pump to start mixing. At this time, the molar ratio of diethyl phosphite to n-butyraldehyde in the mixed material was 1:2, and the dispersion scale of the micro mixer was 550 μm. After mixing, the reaction liquid entered the oil bath temperature control zone, the reaction coil temperature was controlled at 70°C, the inner diameter of the coil was 2 mm, the reaction residence time of the two streams in the temperature control zone was 8.5 min, and the reaction product was collected at the outlet of the system. The collected samples were analyzed by gas chromatography and combined with the external standard curve to calculate that the yield of 1-hydroxybutyl phosphonic acid diethyl ester was 96.78%, and the conversion rate of diethyl phosphite was 97.76%.
[0036] Embodiment 3:
[0037] The first feed liquid of 0.0055 mol / mL diethyl phosphite and the second feed liquid of 0.012 mol / mL n-butyraldehyde were prepared with tetrahydrofuran as solvent. The amount of potassium tert-butoxide in the first feed liquid was 10% of the amount of diethyl phosphite. The first feed liquid and the second feed liquid were respectively transported to the micro mixer at a flow rate of 4.5 mL / min and 4.0 mL / min by a horizontal flow pump to start mixing. At this time, the molar ratio of diethyl phosphite to n-butyraldehyde in the mixed material was 1:1.94, and the dispersion scale of the micro mixer was 550 μm. After mixing, the reaction liquid entered the oil bath temperature control zone, the reaction coil temperature was controlled at 65°C, the inner diameter of the coil was 2 mm, the reaction residence time of the two streams of materials in the temperature control zone was 15.0 min, and the reaction product was collected at the outlet of the system. The collected samples were analyzed by gas chromatography and combined with the external standard curve to calculate that the yield of 1-hydroxybutyl phosphonic acid diethyl ester was 96.43%, and the conversion rate of diethyl phosphite was 96.91%.
[0038] Comparative Example 1:
[0039] Compared with Example 3, the only difference is the concentration of n-butyraldehyde in the second feed solution:
[0040] The first feed liquid of 0.0055 mol / mL diethyl phosphite and the second feed liquid of 0.0065 mol / mL n-butyraldehyde were prepared with tetrahydrofuran as solvent. The amount of potassium tert-butoxide in the first feed liquid was 10% of the amount of diethyl phosphite. The first feed liquid and the second feed liquid were respectively transported to the micro mixer at a flow rate of 4.5 mL / min and 4.0 mL / min by a horizontal flow pump to start mixing. At this time, the molar ratio of diethyl phosphite to n-butyraldehyde in the mixed material was 1:1.05, and the dispersion scale of the micro mixer was 550 μm. After mixing, the reaction liquid entered the oil bath temperature control zone, the reaction coil temperature was controlled at 65°C, the inner diameter of the coil was 2 mm, the reaction residence time of the two streams of materials in the temperature control zone was 15.0 min, and the reaction product was collected at the outlet of the system. The collected samples were analyzed by gas chromatography and combined with the external standard curve to calculate that the yield of 1-hydroxybutyl phosphonic acid diethyl ester was 77.33%, and the conversion rate of diethyl phosphite was 78.91%.
[0041] Comparative Example 2:
[0042] Compared with Example 2, the only difference is that the amount of potassium tert-butoxide added to the first feed liquid is different:
[0043] Tetrahydrofuran was used as a solvent to prepare a first feed liquid of 0.008 mol / mL diethyl phosphite and a second feed liquid of 0.016 mol / mL n-butyraldehyde. The amount of potassium tert-butoxide in the first feed liquid was 4% of the amount of diethyl phosphite. The first feed liquid and the second feed liquid were respectively transported to a micro mixer at a flow rate of 4.0 mL / min and 4.0 mL / min by a horizontal flow pump to start mixing. At this time, the molar ratio of diethyl phosphite to n-butyraldehyde in the mixed material was 1:2, and the dispersion scale of the micro mixer was 550 μm. After mixing, the reaction liquid entered the oil bath temperature control zone, the reaction coil temperature was controlled at 70°C, the inner diameter of the coil was 2 mm, and the reaction residence time of the two streams of materials in the temperature control zone was 8.5 min. The reaction product was collected at the outlet of the system. The collected samples were analyzed by gas chromatography and combined with the external standard curve to calculate that the yield of 1-hydroxybutylphosphonic acid diethyl ester was 66.68%, and the conversion rate of diethyl phosphite was 67.78%.
[0044] Comparative Example 3:
[0045] Compared with Example 1, the only difference is that the reaction temperature during the reaction is different:
[0046] The first feed liquid of 0.003 mol / mL diethyl phosphite and the second feed liquid of 0.008 mol / mL n-butyraldehyde were prepared with tetrahydrofuran as solvent. The amount of potassium tert-butoxide in the first feed liquid was 13% of the amount of diethyl phosphite. The first feed liquid and the second feed liquid were respectively transported to the micro mixer at a flow rate of 4.2 mL / min and 2.9 mL / min by a horizontal flow pump to start mixing. At this time, the molar ratio of diethyl phosphite to n-butyraldehyde in the mixed material was 1:1.84, and the dispersion scale of the micro mixer was 450 μm. After mixing, the reaction liquid entered the oil bath temperature control zone, the reaction coil temperature was controlled at 30°C, the inner diameter of the coil was 2 mm, the reaction residence time of the two streams of materials in the temperature control zone was 10.8 min, and the reaction product was collected at the outlet of the system. The collected samples were analyzed by gas chromatography and combined with the external standard curve to calculate the yield of 1-hydroxybutylphosphonic acid diethyl ester to be 75.74%, and the conversion rate of diethyl phosphite was 76.56%.
[0047] Comparative Example 4:
[0048] Compared with Example 1, the only difference is that the reaction time during the reaction is different:
[0049] The first feed liquid of 0.003 mol / mL diethyl phosphite and the second feed liquid of 0.008 mol / mL n-butyraldehyde were prepared with tetrahydrofuran as solvent. The amount of potassium tert-butoxide in the first feed liquid was 13% of the amount of diethyl phosphite. The first feed liquid and the second feed liquid were respectively transported to the micro mixer at a flow rate of 4.2 mL / min and 2.9 mL / min by a horizontal flow pump to start mixing. At this time, the molar ratio of diethyl phosphite to n-butyraldehyde in the mixed material was 1:1.84, and the dispersion scale of the micro mixer was 450 μm. After mixing, the reaction liquid entered the oil bath temperature control zone, the reaction coil temperature was controlled at 65°C, the inner diameter of the coil was 2 mm, the reaction residence time of the two streams of materials in the temperature control zone was 3 minutes, and the reaction product was collected at the outlet of the system. The collected samples were analyzed by gas chromatography and combined with the external standard curve to calculate the yield of 1-hydroxybutylphosphonic acid diethyl ester to be 75.14%, and the conversion rate of diethyl phosphite was 76.16%.
[0050] The results of the above examples show that the concentration of diethyl phosphite in the first feed liquid is controlled to be 0.002-0.01 mol / mL, the concentration of n-butyraldehyde in the second feed liquid is 0.003-0.03 mol / mL, and the amount of potassium tert-butoxide is 5%-20% of the amount of the reactant diethyl phosphite; and the reaction temperature is controlled at 50°C-80°C; when the reaction time is controlled at 5min-15min, the product yield is good and the raw material conversion rate is high; compared with the existing technology, the time is short, continuous synthesis is possible, and the yield of 1-hydroxybutylphosphonic acid diethyl ester can reach more than 95%.
[0051] The above-mentioned embodiments only express several implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. For ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.
Claims
1. A method for continuously synthesizing diethyl 1-hydroxybutylphosphonate, characterized in that: The steps include: 1) dissolving diethyl phosphite and potassium tert-butoxide in tetrahydrofuran solution to prepare a first feed liquid; dissolving n-butyraldehyde in tetrahydrofuran solution to prepare a second feed liquid; 2) continuously pumping the first feed liquid and the second feed liquid into a micro mixer to mix them to obtain a mixed material; 3) The mixed material is transported to a reaction coil and maintained at a reaction temperature to react to obtain a liquid containing a reaction product.
2. The method according to claim 1, characterized in that: In step 1), the concentration of n-butyraldehyde in the second liquid is in the range of 0.003-0.03 mol / mL, the concentration of diethyl phosphite in the first liquid is in the range of 0.002-0.01 mol / mL, and the amount of potassium tert-butoxide is 5wt%-20wt% of the amount of diethyl phosphite.
3. The method according to claim 1, characterized in that: In step 2), the flow rate of the first liquid is 4.0-8.0 mL / min; the flow rate of the second liquid is 2.0-6.0 mL / min, and the molar ratio of diethyl phosphite to n-butyraldehyde in the mixed material is 1:(1.5-3).
4. The method according to claim 1, characterized in that: In step 2), the micro mixer is a T-type micro mixer, and the dispersion scale of the micro mixer is 250-750 μm.
5. The method according to claim 1, characterized in that: In step 2), the temperature of the first liquid and the second liquid when they are mixed in the micro mixer is 40°C to 80°C.
6. The method according to claim 1, characterized in that: In the step 2), both the first liquid feed and the second liquid feed are transported by a horizontal flow pump, and a one-way valve is provided between the horizontal flow pump and the micro mixer.
7. The method according to claim 1, characterized in that: In step 3), the reaction temperature is 50° C. to 80° C., and the reaction time is 5 min to 15 min.
8. The method according to claim 1, characterized in that: In step 3), the inner diameter of the reaction coil is 1.5 mm to 3 mm, and the material used for the reaction coil is 316L stainless steel.