Method for preparing warfarin by microchannel reactor

Abstract

The invention relates to a method for preparing warfarin by a microchannel reactor. The method comprises the following steps: respectively injecting a mixed solution of o-hydroxyacetophenone, PEG6000, sodium methoxide and toluene and a mixed solution of toluene and dimethyl carbonate into a micro-mixer, mixing, enabling the mixed solution to enter a first module of a micro-channel reactor for reaction, and enabling the reacted solution to flow into a second module of the micro-channel reactor; injecting a mixed solution of benzalacetone and ethanol into the second module group to react with a product flowing out of the first module group, and flowing into the third module group after the reaction; and respectively injecting a hydrochloric acid solution and ethyl acetate into the third module group to react with the intermediate product flowing out of the second module group, enabling the reacted solution to flow into an aqueous solution containing saturated sodium chloride, and performing post-treatment on an organic phase to obtain warfarin. The method has the advantages of low production cost, environmental friendliness, simple process, and high yield and purity of warfarin.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing warfarin using a microchannel reactor. Background Technology

[0002] Warfarin is a coumarin anticoagulant that inhibits the synthesis of vitamin K-related clotting factors II, VII, IX, and X in the liver. It does not counteract existing clotting factors II, VII, IX, and X in the blood. Therefore, it cannot be used as an in vitro anticoagulant, and its in vivo anticoagulation effect requires the depletion of active clotting factors. Its effect is also relatively long-lasting. It is primarily used for the prevention and treatment of thromboembolic diseases.

[0003] Currently, the main industrial method for synthesizing warfarin is the distribution synthesis method, using salicylic acid as a raw material. It is first esterified with methanol, then acylated with acetic anhydride at 40°C, and then acidified under the action of metallic sodium to synthesize 4-hydroxycoumarin; or 4-hydroxycoumarin is obtained by acylation, cyclization, and acidification of salicylic acid and thionyl chloride. Alternatively, substituted butene-[3]-one-[2] is prepared by condensation of benzaldehyde and acetone in the presence of sodium hydroxide. The obtained 4-hydroxycoumarin and substituted butene-[3]-one-[2] are refluxed in pyridine, acidified with hydrochloric acid to pH about 2, left to stand, solidified, and recrystallized to obtain warfarin. This type of synthesis is environmentally polluting, has a complex process and low yield, so there is an urgent need to develop a new method with low production cost, environmental friendliness and simple process. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing warfarin using a microchannel reactor, in order to solve the problems existing in the prior art.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0006] This invention provides a method for preparing warfarin using a microchannel reactor, comprising the following steps:

[0007] (1) A mixed solution of o-hydroxyacetophenone, PEG6000, sodium methoxide and toluene is used as reaction solution 1, and a mixed solution of toluene and dimethyl carbonate is used as reaction solution 2. Reaction solution 1 and reaction solution 2 are injected into the micro mixer for mixing. After mixing, they enter the first module in the microchannel reactor for reaction. After the reaction, they flow into the second module.

[0008] (2) A mixed solution of benzyl acetone and ethanol is used as reaction solution 3. Reaction solution 3 is injected into the second group of modules to react with the intermediate product flowing out of the first group of modules. After the reaction, it flows into the third group of modules.

[0009] (3) Hydrochloric acid solution and ethyl acetate were injected into the third module and reacted with the intermediate product flowing out of the second module. After the reaction was completed, the crude product was collected at the outlet of the third module with saturated sodium chloride aqueous solution and then post-processed to obtain warfarin.

[0010] Optionally, in reaction solution 1, the ratio of o-hydroxyacetophenone to toluene is 0.2–0.4 mol: 200 mL, the ratio of PEG6000 to toluene is 0.4–0.8 g: 200 mL, and the ratio of sodium methoxide to toluene is 0.3–0.6 mol: 200 mL; in reaction solution 2, the ratio of dimethyl carbonate to toluene is 0.25–0.5 mol: 50 mL; and the molar ratio of o-hydroxyacetophenone, sodium methoxide, and dimethyl carbonate is 0.2–0.4: 0.4–0.8: 0.25–0.5.

[0011] Optionally, the flow rate of reaction solution 1 injected into the micromixer is 9–11 mL / min; the flow rate of reaction solution 2 injected into the micromixer is 9–11 mL / min.

[0012] Optionally, the reaction temperature in step (1) is 80-120°C, the travel time of reaction liquid 1 and reaction liquid 2 in the first group module is 1.7-2.1 min, and after 1.7-2.1 min they flow into the second group module.

[0013] Optionally, the molar ratio of o-hydroxyacetophenone to benzyl acetone is 1:1 to 2; the molar ratio of benzyl acetone to ethanol is 0.2 to 0.4 mol: 250 mL; and the flow rate of the reaction solution 3 injected into the second module is 9 to 11 mL / min.

[0014] Optionally, the reaction temperature in step (2) is 80-120°C, the reaction solution 3 and the intermediate product flowing out of the first group module have a travel time of 0.6-3 min in the second group module, and then flow into the third group module after 0.6-3 min.

[0015] Optionally, the flow rate of the hydrochloric acid solution injected into the third module is 9-11 mL / min, and the flow rate of the ethyl acetate injected into the third module is 9-11 mL / min; the concentration of the hydrochloric acid solution is 1-3 mol / L, and the volume ratio of the hydrochloric acid solution to the ethyl acetate is 1:1-1.5.

[0016] Optionally, the reaction temperature in step (3) is 45-60°C, and the travel time of the hydrochloric acid solution, ethyl acetate, and intermediate product flowing out of the second module in the third module is 1-1.5 min. After 1-1.5 min, the intermediate product flows into the saturated sodium chloride aqueous solution.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] This invention divides a microchannel reactor into three modules. The first module is used to synthesize 4-hydroxycoumarin. A toluene solution containing o-hydroxyacetophenone, PEG6000, and sodium methoxide, and a toluene solution containing dimethyl carbonate are injected into a micromixer at a controlled flow rate via a connecting tube. The mixture is then introduced into the first module for reaction at a specific temperature. The first module then injects an ethanol solution of benzyl acetone at a controlled flow rate, and the reaction is carried out at a controlled temperature. The third module injects an aqueous solution of hydrochloric acid and ethyl acetate at a controlled flow rate. After a period of reaction, the solution flows into an aqueous solution containing saturated NaCl. The resulting organic phase is separated, dried, and the solvent is recovered under reduced pressure. Finally, the product is subjected to column chromatography to obtain the target product, warfarin. By controlling the flow rate of the reaction solution entering the microchannel reactor and precisely controlling the residence time of the reaction solution in the microchannel reactor, the reactants are fully contacted, mixed, and reacted within the reactor. This results in high yield and high purity of warfarin. Furthermore, this method requires no catalyst, has low production costs, is environmentally friendly, and has a simple process. Attached Figure Description

[0019] Figure 1 This is a flowchart illustrating the preparation of warfarin using the microchannel reactor of this invention. Detailed Implementation

[0020] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0021] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0022] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0023] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be obvious to those skilled in the art. This application specification and embodiments are merely exemplary.

[0024] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0025] All raw materials used in this invention can be obtained commercially or prepared using existing technologies.

[0026] This invention provides a method for preparing warfarin using a microchannel reactor, comprising the following steps:

[0027] (1) A mixed solution of o-hydroxyacetophenone, PEG6000, sodium methoxide and toluene is used as reaction solution 1, and a mixed solution of toluene and dimethyl carbonate is used as reaction solution 2. Reaction solution 1 and reaction solution 2 are injected into the micro mixer for mixing. After mixing, they enter the first module in the microchannel reactor for reaction. After the reaction, they flow into the second module.

[0028] (2) A mixed solution of benzyl acetone and ethanol is used as reaction solution 3. Reaction solution 3 is injected into the second group of modules to react with the intermediate product flowing out of the first group of modules. After the reaction, it flows into the third group of modules.

[0029] (3) Hydrochloric acid solution and ethyl acetate were injected into the third module and reacted with the intermediate product flowing out of the second module. After the reaction was completed, the crude product was collected at the outlet of the third module with saturated sodium chloride aqueous solution and then post-processed to obtain warfarin.

[0030] Microchannel reactors are continuous flow devices that enhance chemical reaction processes. Their core principle is based on microscale effects, achieving efficient mass and heat transfer through a large specific surface area. Laminar flow and precise mixing improve reaction homogeneity, while continuous flow combined with rapid temperature control significantly optimizes reaction conditions. This technology is mainly applied in pharmaceutical intermediate synthesis, nanomaterial preparation, fine chemicals, and energy catalysis, driving the development of continuous and green chemical processes and becoming a revolutionary technology for modern process intensification and intelligent manufacturing. Compared to traditional synthesis processes, using this technology to synthesize warfarin not only significantly improves the selectivity and yield of each reaction stage, enabling continuous synthesis, but also enhances safety during the synthesis process, reduces waste emissions, and substantially lowers costs.

[0031] In this invention, the ratio of o-hydroxyacetophenone to toluene in reaction solution 1 is 0.2–0.4 mol: 200 mL, preferably 0.3 mol: 200 mL; the ratio of PEG6000 to toluene is 0.4–0.8 g: 200 mL, preferably 0.54–0.6 g: 200 mL; the ratio of sodium methoxide to toluene is 0.3–0.6 mol: 200 mL, preferably 0.4–0.5 mol: 200 mL; the ratio of dimethyl carbonate to toluene in reaction solution 2 is 0.25–0.5 mol: 50 mL, preferably 0.3–0.4 mol: 50 mL; and the molar ratio of o-hydroxyacetophenone, sodium methoxide, and dimethyl carbonate is 0.2–0.4: 0.4–0.8: 0.25–0.5, preferably 0.2: 0.4: 0.3.

[0032] In this invention, the flow rate of reaction solution 1 injected into the micro mixer is 9-11 mL / min, preferably 10 mL / min; the flow rate of reaction solution 2 injected into the micro mixer is 9-11 mL / min, preferably 10 mL / min.

[0033] In this invention, the reaction temperature in step (1) is 80-120°C, and the travel time of reaction liquid 1 and reaction liquid 2 in the first group module is 1.7-2.1 min, preferably 1.9 min, and preferably after 1.9 min, they flow into the second group module.

[0034] In this invention, the molar ratio of o-hydroxyacetophenone to benzyl acetone is 1:1 to 2; preferably 1:1.5. The molar ratio of benzyl acetone to ethanol is 0.2 to 0.4 mol: 250 mL, preferably 0.3 mol: 250 mL. The flow rate of the reaction solution 3 injected into the second module is 9 to 11 mL / min, preferably 10 mL / min.

[0035] In this invention, the reaction temperature in step (2) is 80-120°C, preferably 90-110°C, and more preferably 100°C. The travel time of the reaction liquid 3 and the intermediate product flowing out of the first group module in the second group module is 0.6-3 min, preferably 1.8-2.5 min, and more preferably 2.4 min. It is preferred that the product flows into the third group module after 2.4 min.

[0036] In this invention, the flow rate of the hydrochloric acid solution injected into the third module is 9-11 mL / min, preferably 10 mL / min; the flow rate of the ethyl acetate injected into the third module is 9-11 mL / min, preferably 10 mL / min; the concentration of the hydrochloric acid solution is 1-3 mol / L, preferably 2 mol / L; and the volume ratio of the hydrochloric acid solution to the ethyl acetate is 1:1-1.5, preferably 1:1.

[0037] In this invention, the reaction temperature in step (3) is 45-60°C, preferably 50°C, and the travel time of the hydrochloric acid solution, ethyl acetate, and intermediate product flowing out of the second module in the third module is 1-1.5 min, preferably 1.2 min, and preferably after 1.2 min, it flows into the saturated sodium chloride aqueous solution.

[0038] In an embodiment of the present invention, the post-treatment involves collecting the effluent from the microchannel reactor outlet with a saturated sodium chloride solution, then separating the organic phase and the aqueous phase. The organic phase is then dried, the solvent is recovered under reduced pressure, and column chromatography is performed to obtain the target product, warfarin.

[0039] In an embodiment of the present invention, the microchannel reactor is a Corning G1 microchannel reactor, each module being a heart-shaped tube with a volume of approximately 8.2 mL, and multiple modules can be freely combined into a group as needed.

[0040] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0041] Example 1

[0042] (1) A mixture of 27.23 g o-hydroxyacetophenone, 0.2 mol, 0.54 g PEG6000, 0.4 mol sodium methoxide, and 200 mL toluene solution was injected into a micro mixer at a flow rate of 10 mL / min as reaction solution 1; a mixture of 50 mL toluene solution and 0.3 mol dimethyl carbonate solution was injected into a micro mixer at a flow rate of 2.5 mL / min as reaction solution 2; after reaction solution 1 and reaction solution 2 were mixed in the micro mixer, they entered the first module of the microchannel reactor for reaction; the reaction temperature was 100 °C, and the travel time of reaction solution 1 and reaction solution 2 in the first module was 1.9 min. After 1.9 min, reaction solution 1 and reaction solution 2 completely passed through the first module, generating 4-hydroxycoumarin and entering the second module;

[0043] (2) A mixture of 0.3 mol benzyl acetone and 250 mL ethanol solution was used as reaction solution 3 and injected into the second module of the microchannel reactor at a flow rate of 10 mL / min for reaction. The reaction temperature was 100 °C. The travel time of reaction solution 3 and 4-hydroxycoumarin in the second module was 2.4 min. After 2.4 min, reaction solution 3 and 4-hydroxycoumarin completely passed through the second module, and the intermediate product was obtained and entered the third module.

[0044] (3) 50 mL of 2 M hydrochloric acid aqueous solution and 50 mL of ethyl acetate were simultaneously injected into the third module of the microchannel reactor at a flow rate of 10 mL / min. The reaction temperature was 50 °C. The hydrochloric acid aqueous solution, ethyl acetate and intermediate passed through the third module in 1.2 min. After 1.2 min, the hydrochloric acid aqueous solution, ethyl acetate and intermediate completely passed through the third module. The crude product was collected with saturated NaCl aqueous solution.

[0045] (4) The mixture of crude product and saturated NaCl aqueous solution was stirred, and then the organic phase and aqueous phase were separated. The organic phase was dried, the solvent was recovered under reduced pressure, and column chromatography was used to obtain the target product warfarin.

[0046] Example 2

[0047] The only difference from Example 1 is that a mixture of 0.24 mol benzyl acetone and 250 mL ethanol solution is used as reaction solution 3.

[0048] Example 3

[0049] The only difference from Example 1 is that a mixture of 0.2 mol benzyl acetone and 250 mL ethanol solution is used as reaction solution 3.

[0050] Example 4

[0051] The only difference from Example 1 is that a mixture of 0.4 mol benzyl acetone and 250 mL ethanol solution is used as reaction solution 3.

[0052] Example 5

[0053] The only difference from Example 1 is that the reaction temperature in step (2) is 90°C.

[0054] Example 6

[0055] The only difference from Example 1 is that the reaction temperature in step (2) is 80°C.

[0056] Example 7

[0057] The only difference from Example 1 is that the reaction temperature in step (2) is 110°C.

[0058] Example 8

[0059] The only difference from Example 1 is step (2), where the reaction solution 3 and 4-hydroxycoumarin have a travel time of 0.6 min in the second module.

[0060] Example 9

[0061] The only difference from Example 1 is step (2), where the reaction solution 3 and 4-hydroxycoumarin have a travel time of 1.8 min in the second module.

[0062] Example 10

[0063] The only difference from Example 1 is step (2), where the reaction solution 3 and 4-hydroxycoumarin have a travel time of 3 min in the second module.

[0064] The yield of warfarin was calculated, and its purity was determined by high-performance liquid chromatography (HPLC) with fluorescence detection. The HPLC-fluorescence detection conditions were as follows: a C18 column (4.6 mm × 200 mm, 10 μm) was used; methanol:0.1% phosphoric acid (75:25) was used as the mobile phase; the flow rate was 1.0 mL / min; the detection wavelength was 280 nm; and the emission wavelength was 380 nm. The results are shown in Table 1.

[0065] Table 1. Data on the yield, production rate, and purity of warfarin.

[0066] sample Yield / g Yield / % purity / % Example 1 51.76 84 97 Example 2 47.45 77 97 Example 3 41.90 68 96 Example 4 52.99 86 98 Example 5 43.75 71 97 Example 6 32.66 53 98 Example 7 50.53 82 97 Example 8 26.50 43 96 Example 9 42.52 69 93 Example 10 56.07 91 97

[0067] Table 1 shows that the concentration of the ethanol solution of benzyl acetone affects the yield. Appropriately increasing the concentration of benzyl acetone can accelerate the reaction rate and increase the yield of the target product. The reaction temperature in the second stage also affects the yield. According to reaction kinetics, increasing the temperature can increase the reaction rate and thus the yield of the target product. The reaction path time in the second stage also affects the yield because the reaction time of the reactants in the microchannel reactor is extended, allowing the reaction to proceed more completely and thus increasing the yield of the target product.

[0068] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing warfarin using a microchannel reactor, characterized in that, Includes the following steps: (1) A mixed solution of o-hydroxyacetophenone, PEG6000, sodium methoxide and toluene is used as reaction solution 1, and a mixed solution of toluene and dimethyl carbonate is used as reaction solution 2. Reaction solution 1 and reaction solution 2 are injected into the micro mixer for mixing. After mixing, they enter the first module in the microchannel reactor for reaction. After the reaction, they flow into the second module. (2) A mixed solution of benzyl acetone and ethanol is used as reaction solution 3. Reaction solution 3 is injected into the second group of modules to react with the intermediate product flowing out of the first group of modules. After the reaction, it flows into the third group of modules. (3) Hydrochloric acid solution and ethyl acetate were injected into the third module and reacted with the intermediate product flowing out of the second module. After the reaction was completed, the crude product was collected at the outlet of the third module with saturated sodium chloride aqueous solution and then post-processed to obtain warfarin.

2. The method according to claim 1, characterized in that, In reaction solution 1, the ratio of o-hydroxyacetophenone to toluene is 0.2–0.4 mol: 200 mL, the ratio of PEG6000 to toluene is 0.4–0.8 g: 200 mL, and the ratio of sodium methoxide to toluene is 0.3–0.6 mol: 200 mL; in reaction solution 2, the ratio of dimethyl carbonate to toluene is 0.25–0.5 mol: 50 mL; and the molar ratio of o-hydroxyacetophenone, sodium methoxide, and dimethyl carbonate is 0.2–0.4: 0.4–0.8: 0.25–0.

5.

3. The method according to claim 1, characterized in that, The flow rate of reaction solution 1 injected into the micromixer was 9–11 mL / min; the flow rate of reaction solution 2 injected into the micromixer was 9–11 mL / min.

4. The method according to claim 1, characterized in that, The reaction temperature in step (1) is 80-120℃. The travel time of reaction solution 1 and reaction solution 2 in the first group module is 1.7-2.1 min. After 1.7-2.1 min, they flow into the second group module.

5. The method according to claim 1, characterized in that, The molar ratio of o-hydroxyacetophenone to benzyl acetone is 1:1 to 2; the molar ratio of benzyl acetone to ethanol is 0.2 to 0.4 mol: 250 mL; and the flow rate of the reaction solution 3 injected into the second module is 9 to 11 mL / min.

6. The method according to claim 1, characterized in that, The reaction temperature in step (2) is 80-120℃. The reaction solution 3 and the intermediate product flowing out of the first group module have a travel time of 0.6-3 min in the second group module. After 0.6-3 min, they flow into the third group module.

7. The method according to claim 1, characterized in that, The flow rate of the hydrochloric acid solution injected into the third module is 9–11 mL / min, and the flow rate of the ethyl acetate injected into the third module is 9–11 mL / min; the concentration of the hydrochloric acid solution is 1–3 mol / L, and the volume ratio of the hydrochloric acid solution to the ethyl acetate is 1:1–1.

5.

8. The method according to claim 1, characterized in that, The reaction temperature in step (3) is 45-60℃. The hydrochloric acid solution, ethyl acetate, and intermediate products flowing out of the second module have a travel time of 1-1.5 min in the third module. After 1-1.5 min, they flow into the saturated sodium chloride aqueous solution.

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