Synthesis method of 3-hydroxytetrahydrofuran

Abstract

The invention relates to a synthesis method of 3-hydroxytetrahydrofuran, which comprises the following steps: 1, reduction reaction: adding S-4-chloro-3-hydroxybutyric acid ethyl ester, 95% ethanol and a ruthenium catalyst prepared in the previous step into a reaction kettle, and starting stirring; sealing the reaction kettle, replacing with nitrogen and hydrogen, raising the temperature to 100-110 DEG C and the hydrogen pressure to 1.5-2Mpa, and reacting for 6 hours; after the reaction is finished, filtering and desolventizing to obtain an S-4-chloro-1, 3-butanediol crude product which is directly used for the next step of reaction; 2, cyclization reaction: adding the crude product in the previous step and water into a three-neck bottle, heating to 75-80 DEG C, and reacting for 4 hours; cooling to normal temperature, controlling the pH value to be 9-10 by using a 6% sodium carbonate solution, continuously heating to 80-85 DEG C, and reacting for 6 hours until the pH is not changed; and after the reaction is finished, adding ethanol, desolventizing, extracting twice with ethyl acetate, filtering, desolventizing, and carrying out reduced pressure distillation to obtain the S-3-hydroxytetrahydrofuran with the specific rotation of + 16 degrees to + 20 degrees. The synthesis method is simple and convenient, the process conditions are not harsh, the environmental pollution is less, and the yield is higher.

Description

Technical Field

[0001] This invention relates to a method for synthesizing 3-hydroxytetrahydrofuran. Background Technology

[0002] Optically pure (S)-3-hydroxytetrahydrofuran is an important pharmaceutical intermediate that can be used as an intermediate for the first-line treatment of advanced non-small cell lung cancer (NSCLC) and for the production of afatinib, a raw material for HER2-positive advanced breast cancer. It is an intermediate for afatinib and can also be used in the synthesis of diabetes drug empagliflozin, anti-HIV drugs ampravir and fusanavir.

[0003] Currently, the synthesis of S-3-hydroxytetrahydrofuran uses L-malic acid as a raw material and involves a series of reactions such as esterification, reduction, and intramolecular thermal dehydration and cyclization. Although the raw material cost is low, the purification of the second product, chiral 1,2,4-butanetriol, is extremely difficult. In the high-temperature dehydration and cyclization reaction, there are many byproducts, the yield is not ideal, and the optical purity of the product does not meet the standard.

[0004] Currently, another method uses optically pure ethyl S-4-chloro-3-hydroxybutyrate as a raw material, which is reduced with sodium borohydride to obtain the intermediate S-4-chloro-1,3-butanediol, and then (S)-3-hydroxytetrahydrofuran under acidic conditions. This method uses expensive raw materials, requires large amounts of sodium borohydride, and generates a lot of wastewater.

[0005] The literature (Synthesis, 2013, 45, 931-935) describes a method for converting (R)-3-hydroxytetrahydrofuran to (S)-3-hydroxytetrahydrofuran using the photo-extending reaction of dimethyl azodicarbonate. However, the dimethyl azodicarbonate used in this method is expensive and unsuitable for large-scale production.

[0006] Chinese Patent Publication No. CN110396072A discloses a method for preparing the intermediate chiral 4-chloro-3-hydroxy-1-butanol using 4-chloroacetoacetate as a starting material and a ruthenium complex. This method requires the intermediate to be extracted and purified. The intermediate has good water solubility, but extraction and purification are difficult, making it impossible to scale up production. Summary of the Invention

[0007] The present invention addresses the problems existing in the prior art, namely, the technical problem to be solved by the present invention is to provide a method for synthesizing 3-hydroxytetrahydrofuran.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is: a method for synthesizing 3-hydroxytetrahydrofuran, comprising the following steps: Step S1, First reduction reaction: Step S11: Add S-4-chloro-3-hydroxybutyrate ethyl ester, 95% ethanol, and the ruthenium catalyst prepared in the previous step to the reaction vessel, and start stirring; Step S12: Seal the reactor, purge with nitrogen three times, purge with hydrogen three times, then raise the temperature to 100-110℃, hydrogen pressure 1.5-2 MPa, and react for 6 hours. Step S13: After the reaction is complete, filter and remove solvent to obtain crude S-4-chloro-1,3-butanediol, which can be used directly in the next reaction. Step S2, the second cyclization reaction: Step S21: Add the crude product from the previous step and water to the three-necked flask, heat to 75-80℃, and react for 4 hours; Step S22: Cool to room temperature, use 6% sodium carbonate solution to control the pH value at 9-10, and continue to heat to 80-85℃ for 6 hours until the pH no longer changes; Step S23: After the reaction is complete, ethanol is added, the solvent is removed, and the mixture is extracted twice with ethyl acetate. After filtration, the solvent is removed, and the mixture is distilled under reduced pressure to obtain S-3-hydroxytetrahydrofuran with a specific rotation of +16° to +20°.

[0009] Furthermore, in step S11, the amount of ethyl S-4-chloro-3-hydroxybutyrate added is 300g (1.8mol), the amount of 95% ethanol added is 600g (2m / m), and the amount of ruthenium catalyst prepared in the previous step is 3g (1%).

[0010] Furthermore, in step S12, after 6 hours of reaction, the required index is: ethyl S-4-chloro-3-hydroxybutyrate ≤ 1.0%.

[0011] Further, in step S13, the solvent is removed to obtain 220g of crude S-4-chloro-1,3-butanediol.

[0012] Furthermore, in step S21, the amount of crude product added in the previous step is 220g, 1.77mol, and the amount of water added is 220g, 1m / m.

[0013] Furthermore, in step S23, 660g of ethanol (3 m / m) is added; and the mixture is extracted twice with 550g of ethyl acetate (2.5 m / m).

[0014] Furthermore, in step S23, vacuum distillation yields 111g of S-3-hydroxytetrahydrofuran, with a yield of 70% and a gas phase purity of 99.5%.

[0015] Furthermore, in step S23, the specific curl is 18°.

[0016] Compared with the prior art, the present invention has the following advantages: the synthesis method of the present invention is simple and the process conditions are not harsh, it causes less environmental pollution, has a higher yield, avoids the use of difficult-to-handle reagents such as sodium borohydride, and the catalyst used for reduction can be reused, minimizing the complexity and cost related to the process steps, and is suitable for industrial production. Attached Figure Description

[0017] Figure 1 This is the reaction formula of the present invention. Detailed Implementation

[0018] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.

[0019] In the description of this invention, it should be understood that the terms "longitudinal", "lateral", "up", "down", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings, and are only for the convenience of describing this invention, and are not intended to indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as a limitation of this invention.

[0020] like Figure 1 As shown, the present invention discloses a method for synthesizing 3-hydroxytetrahydrofuran, the reaction formula of which is as follows: in: Formula I: Ethyl S-4-chloro-3-hydroxybutyrate; Formula II: S-4-chloro-1,3-butanediol; Formula III: S-3-hydroxytetrahydrofuran.

[0021] The synthesis method includes the following steps: Step S1, First reduction reaction: Step S11: Add S-4-chloro-3-hydroxybutyrate ethyl ester (300g, 1.8mol), 95% ethanol (600g, 2m / m), and the ruthenium catalyst prepared in the previous step (3g, 1%) to the reactor, and start stirring in the reactor; Step S12: Seal the reactor, purge with nitrogen three times, then purge with hydrogen three times, raise the temperature to 100-110℃, maintain hydrogen pressure at 1.5-2 MPa, and react for 6 hours (requirement: S-4-chloro-3-hydroxybutyrate ethyl ester ≤ 1.0%). Step S13: After the reaction is complete, filter and remove solvent to obtain 220g of crude S-4-chloro-1,3-butanediol, which can be used directly in the next step of the reaction; Step S2, the second cyclization reaction: Step S21: Add the crude product (220g, 1.77mol) and water (220g, 1m / m) from the previous step to the three-necked flask, heat to 75-80℃, and react for 4 hours; Step S22: Cool to room temperature, use 6% sodium carbonate solution to control the pH value at 9-10, and continue to heat to 80-85℃ for 6 hours until the pH no longer changes; Step S23: After the reaction is complete, add ethanol (660g, 3m / m), remove solvent, extract twice with ethyl acetate (550g, 2.5m / m), filter, remove solvent, and distill under reduced pressure to obtain 111g of S-3-hydroxytetrahydrofuran (yield 70%, gas phase purity 99.5%) with a specific rotation of +16° to +20°, preferably 18°.

[0022] Example 1-1 Modified ruthenium catalyst: 0.188 g of copper nitrate (Cu(NO3)2) and 0.175 g of cobalt chloride (CoCl2) were added and diluted with water to 40 mL. The pH of the prepared solution was adjusted to 6.0 with a 10% sodium carbonate aqueous solution. The prepared solution was impregnated onto 2.4 g of 10% ruthenium carbon catalyst support, and the resulting wet solid was placed in a fixed bed and calcined at 180 °C for 6 hours under nitrogen protection. Activation was then carried out by heating to 200 °C with a hydrogen-nitrogen mixture for 4 hours. After cooling to room temperature, the catalyst was washed with pure water until chlorine-free and dried to obtain the desired catalyst. The ruthenium salt content of the catalyst was determined by inductively coupled plasma atomic emission spectrometry (ICP-AES).

[0023] Examples 1-2 Under nitrogen protection, ethyl S-4-chloro-3-hydroxybutyrate (300g, 1.8mol) and 95% ethanol (600g, 2m / m) were added to a 2L high-pressure reactor. Ruthenium catalyst (3g, 1%) prepared in the previous step was added, and stirring was started. The reactor was sealed and purged with nitrogen three times, followed by hydrogen purging three times. The temperature was then slowly increased using a high-low temperature integrated reactor until the reactor temperature reached 100-110℃. The hydrogen pressure was slowly increased to 1.5-2 MPa, and the reaction was continued for 6 hours until the hydrogen pressure stopped decreasing, indicating hydrogenation was complete. The reactor was then cooled to room temperature, and samples were taken through a bottom tube, filtered, and sent for GC analysis (requirement: ethyl S-4-chloro-3-hydroxybutyrate ≤ 1.0%). After the sample passed the test, the pressure inside the reactor was released into the absorption tower. The high-pressure reactor was opened, and the material was released. The catalyst was filtered out by vacuum filtration and washed once with 300 ml of ethanol. The catalyst was collected and the filtrate was desolventized under reduced pressure at 45°C to obtain 220 g of crude S-4-chloro-1,3-butanediol, which was pale yellow in appearance and was directly used in the next reaction step.

[0024] Examples 1-3 Add 220g (1.77mol) of crude S-4-chloro-1,3-butanediol and 220g (1m / m) of water to a 1L three-necked flask (with a reflux condenser). Turn on the stirrer and heat the mixture to 75-80℃ using an oil bath. React for 4 hours. Cool the mixture to room temperature with ice water. Add 6% sodium carbonate solution dropwise to the reaction mixture to adjust the pH to 9.0-10.0. Continue heating the mixture to 80-85℃ and react for 6 hours. During this time, the pH will continuously decrease. Control the pH to 7.0-8.0 by adding sodium carbonate dropwise until the pH stops changing. Take a sample to test for GC. S-4-chloro-1,3-butanediol < 0.5%. The reaction is complete. Add ethanol (660g, 3m / m), desolvent under reduced pressure at 45℃ until no more liquid is produced, then add ethyl acetate (550g, 2.5m / m), filter to remove salt, extract twice, combine the organic phases, desolvent the organic phase under reduced pressure at 45℃ to obtain crude S-3-hydroxytetrahydrofuran, transfer to a 250ml three-necked flask, distill under reduced pressure at 80-100℃ to obtain 111g of S-3-hydroxytetrahydrofuran (yield 70%, gas phase purity 99.5%), appearance: colorless and transparent, specific rotation 18° (+16°~+20°).

[0025] Example 2-1 Modified ruthenium catalyst: 0.376 g of copper nitrate (Cu(NO3)2) and 0.35 g of cobalt chloride (CoCl2) were added, and the solution was diluted with water to 40 mL. The pH of the prepared solution was adjusted to 6.0 with a 10% sodium carbonate aqueous solution. The prepared solution was impregnated onto 2.4 g of a 10% ruthenium carbon catalyst support, and the resulting wet solid was added to a fixed bed and calcined at 180 °C for 6 hours under nitrogen protection. Activation was then carried out by introducing a hydrogen-nitrogen mixture to 200 °C for 4 hours. After cooling to room temperature, the catalyst was washed with pure water until chlorine-free and dried to obtain the desired catalyst. The ruthenium salt content of the catalyst was determined by inductively coupled plasma atomic emission spectrometry (ICP-AES).

[0026] Example 2-2 Under nitrogen protection, ethyl S-4-chloro-3-hydroxybutyrate (300g, 1.8mol) and 95% ethanol (600g, 2m / m) were added to a 2L high-pressure reactor. Ruthenium catalyst (3g, 1%) prepared in the previous step was added, and stirring was started. The reactor was sealed and purged with nitrogen three times, followed by hydrogen purging three times. The temperature was then slowly increased using a high-low temperature integrated reactor until the reactor temperature reached 100-110℃. The hydrogen pressure was slowly increased to 1.5-2 MPa, and the reaction was continued for 5 hours until the hydrogen pressure stopped decreasing, indicating hydrogenation was complete. The reactor was then cooled to room temperature, and samples were taken through a bottom tube, filtered, and sent for GC analysis (requirement: ethyl S-4-chloro-3-hydroxybutyrate ≤ 1.0%). After the sample passed the test, the pressure inside the reactor was released into the absorption tower. The high-pressure reactor was opened, and the material was released. The catalyst was filtered out by vacuum filtration and washed once with 300 ml of ethanol. The catalyst was collected and the filtrate was desolventized under reduced pressure at 45°C to obtain 224 g of crude S-4-chloro-1,3-butanediol, which was pale yellow in appearance and was directly used in the next reaction.

[0027] Example 2-3 Add 224g (1.8mol) of crude S-4-chloro-1,3-butanediol and 224g (1ml) of water to a 1L three-necked flask (with a reflux condenser). Turn on the stirrer and heat the mixture to 75-80℃ using an oil bath. React for 4 hours. Cool the mixture to room temperature with ice water. Add 6% sodium carbonate solution dropwise to the reaction mixture to adjust the pH to 9.0-10.0. Continue heating the mixture to 80-85℃ and react for 6 hours. During this time, the pH will continuously decrease. Control the pH to 7.0-8.0 by adding sodium carbonate dropwise until the pH stops changing. Take a sample to test for GC. S-4-chloro-1,3-butanediol < 0.5%. The reaction is complete. Add ethanol (660g, 3m / m), desolvent under reduced pressure at 45℃ until no more liquid is produced, then add ethyl acetate (550g, 2.5m / m), filter to remove salt, extract twice, combine the organic phases, desolvent the organic phase under reduced pressure at 45℃ to obtain crude S-3-hydroxytetrahydrofuran, transfer to a 250ml three-necked flask, distill under reduced pressure at 80-100℃ to obtain 110g of S-3-hydroxytetrahydrofuran (yield 69%, gas phase purity 98.5%), appearance: colorless and transparent, specific rotation +14.6° (+16°~+20°).

[0028] Example 3-1 Modified ruthenium catalyst: 0.141 g of copper nitrate (Cu(NO3)2) was added, followed by 0.131 g of cobalt chloride (CoCl2). The solution was diluted with water to 40 mL, and the pH was adjusted to 6.0 using a 10% sodium carbonate aqueous solution. The prepared solution was then impregnated onto a 2.4 g 10% ruthenium carbon catalyst support, resulting in a wet solid. This solid was placed in a fixed bed and calcined at 180 °C for 6 hours under nitrogen protection. Activation was then performed by introducing a hydrogen-nitrogen mixture to 200 °C for 4 hours. After cooling to room temperature, the catalyst was washed with pure water until chlorine-free and dried to obtain the desired catalyst. The ruthenium salt content of the catalyst was determined by inductively coupled plasma atomic emission spectrometry (ICP-AES).

[0029] Example 3-2 Under nitrogen protection, ethyl S-4-chloro-3-hydroxybutyrate (300g, 1.8mol) and 95% ethanol (600g, 2m / m) were added to a 2L high-pressure reactor. Ruthenium catalyst (3g, 1%) prepared in the previous step was added, and stirring was started. The reactor was sealed and purged with nitrogen three times, followed by hydrogen purging three times. The temperature was then slowly increased using a high-low temperature integrated reactor until the reactor temperature reached 100-110℃. The hydrogen pressure was slowly increased to 1.5-2 MPa, and the reaction was continued for 6 hours until the hydrogen pressure stopped decreasing, indicating hydrogenation was complete. The reactor was then cooled to room temperature, and samples were taken through a bottom tube, filtered, and sent for GC analysis (requirement: ethyl S-4-chloro-3-hydroxybutyrate ≤ 1.0%). After the sample passed the test, the pressure inside the reactor was released into the absorption tower. The high-pressure reactor was opened, and the material was released. The catalyst was filtered out by vacuum filtration and washed once with 300 ml of ethanol. The catalyst was collected and the filtrate was desolventized under reduced pressure at 45℃ to obtain 210 g of crude S-4-chloro-1,3-butanediol, which was pale yellow in appearance and was directly used in the next reaction.

[0030] Example 3-3 Add 210g (1.69mol) of crude S-4-chloro-1,3-butanediol and 210g (1m / m) of water to a 1L three-necked flask (with a reflux condenser). Turn on the stirrer and heat the mixture to 75-80℃ using an oil bath. React for 4 hours. Cool the mixture to room temperature with ice water. Add 6% sodium carbonate solution dropwise to the reaction mixture to adjust the pH to 9.0-10.0. Continue heating the mixture to 80-85℃ and react for 6 hours. During this time, the pH will continuously decrease. Control the pH to 7.0-8.0 by adding sodium carbonate dropwise until the pH stops changing. Take a sample to test for GC. S-4-chloro-1,3-butanediol < 0.5%. The reaction is complete. Add ethanol (660g, 3m / m), desolvent under reduced pressure at 45℃ until no more liquid is produced, then add ethyl acetate (550g, 2.5m / m), filter to remove salt, extract twice, combine the organic phases, desolvent the organic phase under reduced pressure at 45℃ to obtain crude S-3-hydroxytetrahydrofuran, transfer to a 250ml three-necked flask, distill under reduced pressure at 80-100℃ to obtain 98g of S-3-hydroxytetrahydrofuran (yield 61.8%, gas phase purity 98.5%), appearance: colorless and transparent, specific rotation +17.2° (+16°~+20°).

[0031] The synthesis method of this invention is simple and the process conditions are not harsh, resulting in less environmental pollution. Compared with existing technologies, it has a higher yield and avoids some of the defects associated with existing methods. This invention uses a catalytic hydrogenation reaction and employs ethanol with water removal, avoiding the use of reagents that are difficult to handle with sodium borohydride and large amounts of ethyl acetate. Furthermore, the catalyst can be recycled and reused, minimizing the complexity and cost associated with the process steps, making it suitable for industrial production.

[0032] If this invention discloses or relates to components or structural parts that are fixedly connected to each other, then, unless otherwise stated, a fixed connection can be understood as: a fixed connection that can be detached (e.g., using bolts or screws), or a fixed connection that cannot be detached (e.g., riveting, welding). Of course, a fixed connection can also be replaced by an integral structure (e.g., manufactured in one piece using a casting process) (except where it is obviously impossible to use an integral molding process).

[0033] In addition, unless otherwise stated, the terms used in any of the technical solutions disclosed in this invention to indicate positional relationships or shapes include states or shapes that are similar to, close to, or approximate with those states or shapes.

[0034] Any component provided by this invention can be assembled from multiple individual components or can be a single component manufactured by a one-piece molding process.

[0035] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications can still be made to the specific implementation of the present invention or equivalent substitutions can be made to some technical features without departing from the spirit of the technical solutions of the present invention, and all such modifications and substitutions should be covered within the scope of the technical solutions claimed in the present invention.

Claims

1. A method for synthesizing 3-hydroxytetrahydrofuran, characterized in that: Includes the following steps: Step S1, First reduction reaction: Step S11: Add S-4-chloro-3-hydroxybutyrate ethyl ester, 95% ethanol, and the ruthenium catalyst prepared in the previous step to the reaction vessel, and start stirring; Step S12: Seal the reactor, purge with nitrogen three times, purge with hydrogen three times, then raise the temperature to 100-110℃, hydrogen pressure 1.5-2 MPa, and react for 6 hours. Step S13: After the reaction is complete, filter and remove solvent to obtain crude S-4-chloro-1,3-butanediol, which can be used directly in the next reaction. Step S2, the second cyclization reaction: Step S21: Add the crude product from the previous step and water to the three-necked flask, heat to 75-80℃, and react for 4 hours; Step S22: Cool to room temperature, use 6% sodium carbonate solution to control the pH value at 9-10, and continue to heat to 80-85℃ for 6 hours until the pH no longer changes; Step S23: After the reaction is complete, ethanol is added, the solvent is removed, and the mixture is extracted twice with ethyl acetate. After filtration, the solvent is removed, and the mixture is distilled under reduced pressure to obtain S-3-hydroxytetrahydrofuran with a specific rotation of +16° to +20°.

2. The method for synthesizing 3-hydroxytetrahydrofuran according to claim 1, characterized in that: In step S11, the amount of ethyl S-4-chloro-3-hydroxybutyrate added is 300g (1.8mol), the amount of 95% ethanol added is 600g (2m / m), and the amount of ruthenium catalyst prepared in the previous step added is 3g (1%).

3. The method for synthesizing 3-hydroxytetrahydrofuran according to claim 2, characterized in that: In step S12, after 6 hours of reaction, the required index is: S-4-chloro-3-hydroxybutyrate ethyl ester ≤ 1.0%.

4. The method for synthesizing 3-hydroxytetrahydrofuran according to claim 3, characterized in that: In step S13, the solvent was removed to obtain 220g of crude S-4-chloro-1,3-butanediol.

5. The method for synthesizing 3-hydroxytetrahydrofuran according to claim 1, characterized in that: In step S21, the amount of crude product added in the previous step is 220g, which is 1.77mol, and the amount of water added is 220g, which is 1m / m.

6. The method for synthesizing 3-hydroxytetrahydrofuran according to claim 5, characterized in that: In step S23, 660g of ethanol (3 m / m) was added; and the mixture was extracted twice with 550g of ethyl acetate (2.5 m / m).

7. The method for synthesizing 3-hydroxytetrahydrofuran according to claim 6, characterized in that: In step S23, vacuum distillation yielded 111 g of S-3-hydroxytetrahydrofuran, with a yield of 70% and a gas phase purity of 99.5%.

8. The method for synthesizing 3-hydroxytetrahydrofuran according to claim 6, characterized in that: In step S23, the specific curl is 18°.

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