Synthesis method of Corey lactone diol
The synthesis of Corey lactone diol under ambient temperature and pressure using a microfluidic reactor solves the safety and efficiency problems of the traditional high-pressure, high-temperature Prins reaction, achieving high-yield and high-efficiency synthesis suitable for industrial production.
Patent Information
- Application Number
- CN202511076726.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-01
- Publication Date
- 2025-11-18
AI Technical Summary
Existing methods for synthesizing Corey lactone diols involve long reaction times, cumbersome post-processing steps, excessive waste generation, low yields, and poor safety. In particular, the Prins reaction, conducted under high pressure and high temperature conditions, poses a risk.
Corey lactone diol was synthesized using a microfluidic reactor. The compound was mixed with paraformaldehyde and reacted under ambient temperature and pressure in a microchannel reactor, followed by extraction, hydrolysis and other steps. The reaction conditions were optimized to improve the yield.
It achieves high-yield and high-efficiency synthesis of Corey lactone diol, with improved safety, simple operation, suitability for industrial production, and high chemical yield.
Smart Images
Figure CN120965633A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of biopharmaceutical technology, specifically to a method for synthesizing Corey lactone diol. Background Technology
[0002] Entecavir intermediates are an important class of endogenous substances with multiple biological activities, possessing the advantages of low dosage and high pharmacological activity. Entecavir chiral drugs can be used clinically to treat a variety of diseases, such as congenital heart disease, pulmonary hypertension, peptic ulcers, glaucoma, coagulation disorders, and asthma. Currently marketed entecavir drugs, such as lubiprostone, tafluprost, latanoprost, alprostadil, and misoprostol, have become an important class of drugs.
[0003] Corey lactone diol is an important chiral intermediate in the synthesis of entecavir. Its chemical name is (1R,5S,6S,7S)-(+)-7-hydroxy-6-hydroxymethyl-2-hexaoxybicyclo[3.3.0]octane-3-one, abbreviated as CLA. It plays an extremely important role in the synthesis of entecavir-like drugs.
[0004] Currently, the Prins reaction for synthesizing Corey lactone diol must be carried out in a high-pressure reactor under high-temperature conditions. The high pressure and temperature result in a high risk factor and low conversion rate; therefore, this step in the Prins reaction needs improvement and optimization. Summary of the Invention
[0005] To address the shortcomings of existing technologies, this invention provides a method for synthesizing Corey lactone diol using microfluidic reaction. This method solves a series of problems associated with batch reactors, such as long reaction time, cumbersome post-processing steps, excessive waste generated during post-processing, low yield, poor safety, and poor mass and heat transfer.
[0006] To achieve the above objectives, the present invention provides the following technical solution:
[0007] This invention discloses a method for synthesizing Corey lactone diol, comprising the following steps:
[0008] (1) Prepare reaction solution A by dissolving compound I in acetic acid;
[0009] (2) Prepare reaction solution B by mixing paraformaldehyde with sulfuric acid solution;
[0010] (3) Pump the reaction solution A and the reaction solution B into a mixer respectively, and then pump them into a microchannel reactor through the mixer to carry out the reaction, and obtain the reaction effluent;
[0011] (4) After extracting the reaction effluent, the resulting aqueous phase is subjected to vacuum distillation to obtain a solid; the solid is mixed with an organic solvent and hydrochloric acid and then hydrolyzed to obtain Corey lactone diol;
[0012] The structural formula of compound I is as follows:
[0013] Preferably, in step (1), the concentration of compound I in the reaction solution A is 0.16-0.17 g / mL.
[0014] Preferably, in step (2), the concentration of paraformaldehyde in the reaction solution B is 0.0968 g / mL; and the mass concentration of the sulfuric acid solution is 65%.
[0015] Preferably, in step (3), the rate at which reaction solution A is pumped into the mixer is 0.3-1.0 mL / min; and the rate at which reaction solution B is pumped into the mixer is 1.2-4.0 mL / min.
[0016] Preferably, in step (3), the parameters for the reaction pumped into the microchannel reactor by the mixer are set as follows: the flow rate of the microchannel is 1-2 mL / min; the temperature of the microchannel reactor is 0-20℃; and the pressure is 1-2 MPa.
[0017] Preferably, in step (4), the extraction is performed using ethyl acetate.
[0018] Preferably, in step (4), the organic solvent is methanol; the hydrolysis temperature is 60-100℃ and the time is 2-6h.
[0019] Preferably, the hydrolysis process further includes the following steps: sequential cooling, neutralization with saturated sodium bicarbonate solution, depressurized distillation to remove solvent, dissolving the residue in dichloromethane, hot filtration to remove insoluble matter, and cooling the filtrate.
[0020] Accordingly, a method for improving the yield of Corey lactone diol is provided, employing the aforementioned method for synthesizing Corey lactone diol.
[0021] The present invention has the following beneficial effects:
[0022] 1. The method of this invention enables the synthesis of Corey lactone diol with high yield, high efficiency, and greater safety. The method employs mild reaction conditions, eliminating reaction insecurity and making it more suitable for chemical production. Within the microfluidic reactor, enhanced molecular mixing brings the reaction closer to its intrinsic reaction state, thereby significantly improving the reaction selectivity of the thermodynamically dominant product (1S, 2R, 3S, 5R) configuration Corey lactone diol acetylates, thus enabling more efficient production of Corey lactone diol.
[0023] 2. The method disclosed in this invention has the characteristics of mild reaction conditions, simple operation, simple synthesis route, high chemical yield, and low cost, and is suitable for industrial production. Attached Figure Description
[0024] Figure 1 This is a schematic diagram of the process for synthesizing Corey lactone diol using a microfluidic reactor according to the present invention.
[0025] Figure 2 The liquid chromatogram of Corey lactone diol prepared in Example 2;
[0026] Figure 3 The 1H NMR spectrum of Corey lactone diol prepared in Example 2;
[0027] Figure 4 The image shows the carbon NMR spectrum of Corey lactone diol prepared in Example 2. Detailed Implementation
[0028] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0029] Unless otherwise specified, the technical means used in the implementation examples are conventional means well known to those skilled in the art.
[0030] like Figure 1 As shown, this invention discloses a method for synthesizing Corey lactone diol, comprising the following steps:
[0031] (1) Prepare reaction solution A by dissolving compound I in acetic acid; the concentration of compound I in reaction solution A is 0.16-0.17 g / mL.
[0032] (2) Prepare reaction solution B by mixing paraformaldehyde with sulfuric acid solution; the concentration of paraformaldehyde in reaction solution B is 0.0968 g / mL; the mass concentration of sulfuric acid solution is 65%.
[0033] (3) The reaction solution A and the reaction solution B are pumped into a mixer respectively, and then pumped into a microchannel reactor through the mixer to carry out the reaction, obtaining the reaction effluent; the pumping rate of reaction solution A into the mixer is 0.3-1.0 mL / min; the pumping rate of reaction solution B into the mixer is 1.2-4.0 mL / min. The parameters for the reaction carried out by pumping the mixture into the microchannel reactor are set as follows: the flow rate of the microchannel is 1-2 mL / min; the temperature of the microchannel reactor is 0-20℃; and the pressure is 1-2 MPa.
[0034] (4) After extracting the reaction effluent, the resulting aqueous phase is subjected to vacuum distillation to obtain a solid; the solid is mixed with an organic solvent and hydrochloric acid and then hydrolyzed to obtain Corey lactone diol; the extraction is performed using ethyl acetate. The organic solvent is methanol; the hydrolysis temperature is 60-100℃, and the time is 2-6 hours. The hydrolysis process further includes the following steps: sequential cooling, neutralization with saturated sodium bicarbonate solution, removal of solvent by vacuum distillation, dissolution of the residue with dichloromethane, hot filtration to remove insoluble matter, and cooling of the filtrate.
[0035] Compound I is (1S,5R)-Corey lactone, with the structural formula [structure omitted]. Purchased from Shanghai Dibai Biotechnology Co., Ltd., the compound has a purity of 98%.
[0036] The synthetic route is as follows:
[0037]
[0038] In this invention, the yield of Corey lactone diol gradually increases with the increase of the concentration of compound I in reaction solution A. The yield of Corey lactone diol is the largest when it reaches 0.16-0.17 g / mL. As the concentration of compound I in reaction solution A further increases, the yield of Corey lactone diol shows a decreasing trend. Therefore, the preferred concentration of compound I in reaction solution A in this invention is 0.16-0.17 g / mL.
[0039] This invention controls the molar equivalent of sulfuric acid to 30%-60% of the molar equivalent of compound I by limiting the concentration of sulfuric acid and the pumping rate of reaction solution A and reaction solution B into the mixer.
[0040] In this invention, the yield of Corey lactone diol gradually increases with the increase of microchannel flow rate. However, with a further increase in microchannel flow rate, the yield of Corey lactone diol shows a decreasing trend. Therefore, the preferred microchannel flow rate in this invention is 1-2 mL / min.
[0041] In some specific embodiments of the present invention, reaction solution A and reaction solution B are pumped into a mixer at a certain ratio and flow rate using a horizontal flow pump, mixed, and then injected into a microflow field reactor equipped with a back pressure valve. The feed molar mass ratio (g / mol) of compound I to paraformaldehyde is controlled to be 1:(4-4.2) by adjusting the concentrations of compound I and paraformaldehyde in reaction solution A and reaction solution B, as well as their pumping rates; more preferably, the feed molar mass ratio (g / mol) of compound I to paraformaldehyde is 1:4.
[0042] In some specific embodiments of the present invention, the microchannel reactor has a volume of 1-2 mL, the inner diameter of the reactor coil is 0.5 mm-1 mm, the residence time of the reaction solution is 180 s-240 s, the pressure is 1-2 MPa, and the reaction temperature is 0-20 °C. Preferably, the microchannel reactor has a volume of 1.5 mL, a pressure of 1.5 MPa, and a reaction temperature of 20 °C.
[0043] As the hydrolysis temperature increases, the product yield gradually increases; however, with further increases in hydrolysis temperature, the product yield remains unchanged. Similarly, as the hydrolysis time increases, the product yield gradually increases; however, with further increases in hydrolysis time, the product yield remains unchanged. Therefore, in a preferred embodiment of the present invention, the organic solvent is methanol; the hydrolysis temperature is 60-100℃, and the time is 2-6 hours; more preferably, the hydrolysis is specifically performed by stirring and heating under reflux at 85-95℃ for 4 hours.
[0044] In this invention, the reaction effluent contains compound II; the mass ratio of hydrochloric acid to compound II is 1:(1-7), preferably, the mass ratio of hydrochloric acid to compound II is 1:(1-5).
[0045] The structural formula of compound II is:
[0046] In a preferred embodiment of the present invention, the hydrolysis process further includes the following steps: sequential cooling, neutralization with saturated sodium bicarbonate solution, removal of solvent by depressurized distillation, dissolution of the residue with dichloromethane, hot filtration to remove insoluble matter, and cooling of the filtrate.
[0047] This invention does not impose any particular limitation on the source of the raw materials and reagents used; commercially available products well known to those skilled in the art can be used.
[0048] The method of this invention replaces the high temperature and high pressure environment of the traditional Prins reaction, enabling the Prins reaction to be carried out at room temperature and pressure. It is simple to operate, has a high safety factor, and is more suitable for industrial production.
[0049] The present invention will be further illustrated by the following examples.
[0050] Example 1
[0051] Step 1, Synthesis of Compound II
[0052] 5g of compound I was dissolved in 30mL of acetic acid to prepare reaction solution A. 9.68g of paraformaldehyde was dissolved in 100mL of 65% sulfuric acid solution to prepare reaction solution B. Reaction solution A was pumped into a mixer at a rate of 0.5mL / min, and reaction solution B at a rate of 2mL / min, respectively. After passing through the mixer, the solutions were pumped into a microchannel reactor for mixing. The flow rate of the microchannel reactor was set to 1mL / min, the temperature was set to 20℃, and the pressure was approximately 1.5MPa. The effluent contained compound II. In the above reaction, the molar ratio of compound I to polymethyl methacrylate (PMMA) was 1:4.
[0053] Step 2, Synthesis of Corey lactone diol
[0054] The reaction effluent obtained above was neutralized to pH 5.5 (5-6 is also acceptable) with 45% sodium hydroxide solution. The aqueous phase was then extracted with ethyl acetate (25 mL × 3). The aqueous phase was retained and then subjected to vacuum distillation to remove the solvent water. 30 mL of methanol was added to the remaining white solid and placed in a 100 mL three-necked flask. 3 mL of hydrochloric acid was added, and the mixture was stirred and heated under reflux for 4 h. The reaction solution was then cooled to 0 °C in an ice-salt bath and neutralized to pH 4 with saturated sodium bicarbonate solution. The solvent was removed by vacuum distillation. The residue was dissolved in dichloromethane, and the insoluble matter was removed by hot filtration. After cooling the filtrate, 5.79 g of white solid precipitated, which was Corey lactone diol. The overall yield of the reaction was 83.5%.
[0055] Example 2
[0056] Step 1, Synthesis of Compound II
[0057] 5g of compound I was dissolved in 30mL of acetic acid to prepare reaction solution A. 9.68g of paraformaldehyde was dissolved in 100mL of 65% sulfuric acid solution to prepare reaction solution B. Reaction solution A was pumped into a mixer at a rate of 0.5mL / min, and reaction solution B at a rate of 2mL / min, respectively. After passing through the mixer, the mixture was then pumped into a microchannel reactor for further mixing. The flow rate of the microchannel was set to 1.5mL / min, the temperature of the microchannel reactor was set to 20℃, and the pressure was approximately 1.5MPa. The effluent contained compound II. In the above reaction, the molar ratio of compound I to polymethyl methacrylate (PMMA) was 1:4.
[0058] Step 2, Synthesis of Corey lactone diol
[0059] The reaction effluent obtained above was neutralized to pH 5.5 (5-6 is also acceptable) with 45% sodium hydroxide solution. The aqueous phase was then extracted with ethyl acetate (25 mL × 3). The aqueous phase was retained and then subjected to vacuum distillation to remove the solvent water. 30 mL of methanol was added to the remaining white solid and placed in a 100 mL three-necked flask. 3 mL of hydrochloric acid was added, and the mixture was stirred and heated under reflux for 4 h. The reaction solution was then cooled to 0 °C in an ice-salt bath and neutralized to pH 4 with saturated sodium bicarbonate solution. The solvent was removed by vacuum distillation. The residue was dissolved in dichloromethane, and the insoluble matter was removed by hot filtration. After cooling the filtrate, 6.06 g of white solid precipitated, which was Corey lactone diol. The overall yield of the reaction was 87.4%.
[0060] The liquid chromatogram of the Corey lactone diol prepared in this embodiment is shown below. Figure 2 As shown; the 1H NMR spectrum is as follows Figure 3 As shown; the carbon NMR spectrum is as follows. Figure 4 As shown.
[0061] Example 3
[0062] Step 1, Synthesis of Compound II
[0063] 5g of compound I was dissolved in 30mL of acetic acid to prepare reaction solution A. 9.68g of paraformaldehyde was dissolved in 100mL of 65% sulfuric acid solution to prepare reaction solution B. Reaction solution A was pumped into a mixer at a rate of 0.5mL / min, and reaction solution B at a rate of 2mL / min, respectively. After passing through the mixer, the mixture was pumped into a microchannel reactor for further mixing. The flow rate of the microchannel was set to 2mL / min, the temperature of the microchannel reactor was set to 20℃, and the pressure was approximately 1.5MPa. The effluent contained compound II. In the above reaction, the molar ratio of compound I to polymethyl methacrylate (PMMA) was 1:4.
[0064] Step 2, Synthesis of Corey lactone diol
[0065] The reaction effluent obtained above was neutralized to pH 5.5 (5-6 is also acceptable) with 45% sodium hydroxide solution. The aqueous phase was then extracted with ethyl acetate (25 mL × 3). The aqueous phase was retained and then subjected to vacuum distillation to remove the solvent water. 30 mL of methanol was added to the remaining white solid and placed in a 100 mL three-necked flask. 3 mL of hydrochloric acid was added, and the mixture was stirred and heated under reflux for 4 h. The reaction solution was then cooled to 0 °C in an ice-salt bath and neutralized to pH 4 with saturated sodium bicarbonate solution. The solvent was removed by vacuum distillation. The residue was dissolved in dichloromethane, and the insoluble matter was removed by hot filtration. After cooling the filtrate, 5.86 g of white solid precipitated, which was Corey lactone diol. The overall yield of the reaction was 84.6%.
[0066] This invention discloses a method for preparing Corey lactone diol using a microfluidic reactor. Utilizing the Prins reaction system with a backpressure-regulated microfluidic field, it offers excellent molecular mixing and collision opportunities, significantly improving molecular-level reaction selectivity and enhancing the efficient synthesis of the dominant configuration of the main product. The improved process significantly enhances safety and environmental friendliness, simplifies post-processing, and is environmentally friendly.
[0067] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.
Claims
1. A method for synthesizing Corey lactone diol, characterized in that: Includes the following steps: (1) Prepare reaction solution A by dissolving compound I in acetic acid; (2) Prepare reaction solution B by mixing paraformaldehyde with sulfuric acid solution; (3) Pump the reaction solution A and the reaction solution B into a mixer respectively, and then pump them into a microchannel reactor through the mixer to carry out the reaction, and obtain the reaction effluent; (4) After extracting the reaction effluent, the resulting aqueous phase is subjected to vacuum distillation to obtain a solid; the solid is mixed with an organic solvent and hydrochloric acid and then hydrolyzed to obtain Corey lactone diol; The structural formula of compound I is as follows:
2. The method for synthesizing Corey lactone diol according to claim 1, characterized in that: In step (1), the concentration of compound I in the reaction solution A is 0.16-0.17 g / mL.
3. The method for synthesizing Corey lactone diol according to claim 1, characterized in that: In step (2), the concentration of paraformaldehyde in the reaction solution B is 0.0968 g / mL; the mass concentration of the sulfuric acid solution is 65%.
4. The method for synthesizing Corey lactone diol according to claim 1, characterized in that: In step (3), the reaction solution A is pumped into the mixer at a rate of 0.3-1.0 mL / min; the reaction solution B is pumped into the mixer at a rate of 1.2-4.0 mL / min.
5. The method for synthesizing Corey lactone diol according to claim 1, characterized in that: In step (3), the parameters for the reaction pumped into the microchannel reactor by the mixer are set as follows: the flow rate of the microchannel is 1-2 mL / min; the temperature of the microchannel reactor is 0-20℃; and the pressure is 1-2 MPa.
6. The method for synthesizing Corey lactone diol according to claim 1, characterized in that: In step (4), the extraction is performed using ethyl acetate.
7. A method for synthesizing Corey lactone diol according to claim 1 or 6, characterized in that: In step (4), the organic solvent is methanol; the hydrolysis temperature is 60-100℃ and the time is 2-6h.
8. The method for synthesizing Corey lactone diol according to claim 1, characterized in that: The hydrolysis process further includes the following steps: sequential cooling, neutralization with saturated sodium bicarbonate solution, depressurized distillation to remove solvent, dissolving the residue in dichloromethane, hot filtration to remove insoluble matter, and cooling the filtrate.
9. A method for improving the yield of Corey lactone diol, characterized in that: The method for synthesizing Corey lactone diol according to any one of claims 1-8 is adopted.