Method for rapidly preparing 3-(3-pyridine) acrylic acid by adopting kettle type one-pot method

Abstract

The invention discloses a method for rapidly preparing 3-(3-pyridine) acrylic acid by adopting a kettle type one-pot method, which comprises the following steps: dropwise adding tert-butyl acetate into a tetrahydrofuran solution of lithium diisopropylamide, then dropwise adding 3-pyridylaldehyde, reacting I, quenching and separating a saturated salt solution, mixing an organic phase and an aqueous alkali solution, stirring, reacting II, filtering, washing and drying to obtain 3-(3-pyridine) acrylic acid. And adding sulfuric acid to neutralize and separate, mixing the organic phase with a sulfuric acid aqueous solution, reacting III, adding sodium hydroxide to neutralize, separating and filtering to obtain the 3-(3-pyridine) acrylic acid. Through optimization of a synthetic route, the 3-(3-pyridine) acrylic acid drug intermediate is synthesized by adopting an efficient, clean and safe three-step kettle type one-pot process without using a pyridine solvent, sodium hydride and other dangerous reagents.

Description

Technical Field

[0001] The present application relates to a method for rapidly preparing 3-(3-pyridine) acrylic acid by a one-pot method, and belongs to the field of chemistry and chemical engineering. Background Art

[0002] 3-(3-pyridine) acrylic acid, CAS: 1126-74-5, is an important intermediate for the synthesis of the drug molecule cedamide. The traditional preparation process of 3-(3-pyridine) acrylic acid is mainly based on the autoclave Knoevenagel condensation reaction, which uses 3-pyridinealdehyde and malonic acid under the catalysis of piperidine, pyridine as a solvent / acid binder, and a two-step reaction of condensation and decarboxylation at high temperature in one pot. However, the foul odor of pyridine not only seriously endangers human health, but the discharge of waste solvents will also cause serious pollution to the water environment. Therefore, it is very important to develop a clean autoclave synthesis process route that replaces pyridine as a solvent.

[0003] Perkin reaction is one of the synthetic methods for preparing α,β-unsaturated olefinic acids. Kettenes et al. [Recueil, 1955, vol 74, p.1049-1055] used 3-pyridinealdehyde and acetic anhydride as raw materials to prepare 3-(3-pyridine) acrylic acid in one pot under solvent-free conditions and high temperature of 180-190°C. However, Perkin reaction not only requires extremely high reaction temperature, but also has a synthetic yield of only 29%. The brown color of the product indicates that its purity is low and has no application value.

[0004] In the invention patent CN103221413B, tetrahydrofuran is used as a solvent, and diethoxyphosphate-ethyl acetate and 3-pyridine aldehyde are used to first generate 3-(3-pyridine) ethyl acrylate under the catalysis of sodium hydride. The crude product is subjected to vacuum distillation and column chromatography post-treatment, and then hydrolyzed in a sodium hydroxide solution to generate 3-(3-pyridine) acrylic acid, with a total yield of 80%. However, since flammable and explosive sodium hydride is used as a base in the synthesis process, the process safety is difficult to ensure; in addition, the 3-(3-pyridine) ethyl acrylate generated in the first step of the reaction needs to be subjected to complex post-treatment before it can be used for the second step of hydrolysis, which is not conducive to rapid and efficient production on an industrial scale.

[0005] In addition, Denonne et al. [Bioorganic & Medicinal Chemistry Letters, 2007, vol17, #12, p.3262-3265] used 3-bromopyridine and methyl acrylate as raw materials, N,N-dimethylamide as solvent, and directly coupled the Heck reaction to prepare 3-(3-pyridine) acrylic acid under the catalysis of palladium catalyst. However, due to the high cost of palladium catalyst and the easy generation of phosphorus-containing wastewater that is difficult to treat, further increasing its post-processing cost, the industrial value of this route is very limited. Summary of the invention

[0006] The purpose of the present invention is to solve the problems of environmental pollution, low efficiency, poor safety and high cost in the existing 3-(3-pyridine) acrylic acid synthesis route, and to use tetrahydrofuran and water as full-process solvents to efficiently and concisely realize the three-step one-pot reaction of Aldol condensation, hydrolysis and dehydration in a way that does not require intermediate separation and purification. The synthesis route has high yield, does not use pyridine solvent and other high-boiling point difficult-to-separate solvents and reagents, reduces the discharge of three wastes, does not need to use dangerous sodium hydride reagents, and can obtain high-purity products without complicated post-processing, which is conducive to achieving efficient, clean and safe production.

[0007] According to one aspect of the present application, a method for rapidly preparing 3-(3-pyridine)acrylic acid by a one-pot process is provided, characterized in that:

[0008] The following steps are involved:

[0009] Tert-butyl acetate is added dropwise to a tetrahydrofuran solution of lithium diisopropylamide, and then 3-pyridinealdehyde is added dropwise, reaction I is carried out, quenched with a saturated salt solution, separated, the organic phase (i.e., tert-butyl 3-hydroxy-3-(3-pyridine)acrylate solution) is mixed with an alkali aqueous solution, stirred, reaction II is carried out, sulfuric acid is added for neutralization, separated, the organic phase is mixed with an aqueous sulfuric acid solution, reaction III is carried out, sodium hydroxide is added for neutralization, precipitation is carried out, and filtration is carried out to obtain 3-(3-pyridine)acrylic acid.

[0010] The molar ratio of lithium diisopropylamide to tert-butyl acetate is 1.0 to 1.1;

[0011] The molar equivalent ratio of 3-pyridinealdehyde to tert-butyl acetate is 0.8 to 1.0;

[0012] The temperature of the reaction I is -78 to -70°C;

[0013] The reaction time of the reaction I is 15 to 60 minutes;

[0014] The temperature of the dropping process does not exceed -70°C.

[0015] The saturated salt solution is selected from at least one of saturated sodium sulfate, saturated sodium chloride, and saturated potassium sulfate.

[0016] The base is selected from at least one of lithium hydroxide, sodium hydroxide and potassium hydroxide;

[0017] The concentration of the alkaline aqueous solution is 1 to 5 M;

[0018] The temperature of the reaction II is 20-30°C;

[0019] The time of the reaction II is 120 to 240 minutes.

[0020] The concentration of the sulfuric acid aqueous solution is 40-60wt%;

[0021] The temperature of the reaction III is 120-130°C;

[0022] The time of the reaction III is 120 to 240 minutes.

[0023] Specifically, the steps include:

[0024] (1) Aldol condensation reaction

[0025] Under low temperature conditions, tert-butyl acetate is dropped into a certain equivalent of lithium diisopropylamide tetrahydrofuran solution for deprotonation, and then a certain equivalent of 3-pyridinealdehyde is dropped into the deprotonated tert-butyl acetate solution under controlled dropping speed to generate tert-butyl 3-hydroxy-3-(3-pyridine)acrylate. After a certain reaction time, the reaction is restored to room temperature and quenched directly with a saturated sodium sulfate aqueous solution.

[0026] (2) Hydrolysis reaction

[0027] The reaction solution obtained in step (1) is separated into an aqueous phase, and the organic phase is retained. A certain concentration of alkaline aqueous solution is added, and the mixture is stirred at a certain temperature for a certain period of time to generate 3-hydroxy-3-(3-pyridine)acrylic acid, and sulfuric acid is added to neutralize the mixture.

[0028] (3) Dehydration reaction

[0029] The organic phase of the reaction solution obtained in step (2) is separated, and the aqueous phase is retained. A certain concentration of sulfuric acid aqueous solution is added, and after reacting at high temperature for a certain period of time, 3-(3-pyridine)acrylic acid is generated. Sodium hydroxide is added to adjust to neutrality, and the precipitated solid is filtered to obtain the product.

[0030] The reaction route is as follows:

[0031]

[0032] The beneficial effects of this application include:

[0033] The present invention optimizes the synthesis route and designs a method for synthesizing 3-(3-pyridine) acrylic acid pharmaceutical intermediates by using an efficient, clean and safe three-step kettle one-pot process without using dangerous reagents such as pyridine solvents and sodium hydride. The total yield of the synthesis route is greater than 85%, and the product purity is close to 100%. The three-step synthesis process does not require any intermediate purification or separation operations. After the third step of the dehydration reaction is completed, high-purity 3-(3-pyridine) acrylic acid can be quickly precipitated by adjusting the pH value of the solution, which greatly reduces the post-processing operation time, and the total process time is less than 5 hours. The invention also provides a useful reference for the industrial efficient and simple synthesis of α, β unsaturated olefinic acid and its analogs. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The process flow chart of the three-step one-pot method involved in the present invention; DETAILED DESCRIPTION

[0035] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0036] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.

[0037] Example 1

[0038] The experimental process follows Figure 1As shown in the three-step one-pot process flow chart, 100 ml (2M) tetrahydrofuran solution of lithium diisopropylamide is added to a 1000 ml reaction bottle, which is filled with nitrogen for protection. 100 ml of anhydrous tetrahydrofuran is carefully added dropwise at ultra-low temperature (-78°C) to dilute the 2M lithium diisopropylamide solution to 1M, and the temperature of the dilution process is controlled to be lower than -70°C; then 100 ml of a 2M tetrahydrofuran solution of tert-butyl acetate prepared in advance is carefully added dropwise, and the temperature of the addition process is controlled to be lower than -70°C; after the addition is completed, 100 ml of a 2M tetrahydrofuran solution of 3-pyridinealdehyde prepared in advance is added dropwise, and the temperature of the addition process is controlled to be lower than -70°C. After the addition is completed, the reaction is maintained at -78°C for 15 minutes. After returning to room temperature, 400 ml of a saturated sodium sulfate solution is added for quenching, and the mixture is stirred for 15 minutes. The liquid in the kettle is separated into upper and lower layers. The lower aqueous phase was discharged, and the upper organic phase sample was taken for chromatographic analysis. The purity of the product tert-butyl 3-hydroxy-3-(3-pyridine) acrylic acid was 96.3%. At room temperature, 400 ml of 1.0 M LiOH aqueous solution was added, stirred at room temperature for 120 min, sulfuric acid was added to neutralize the liquid in the kettle to neutrality, and the lower aqueous phase sample was taken for chromatographic analysis. The purity of the product 3-hydroxy-3-(3-pyridine) acrylic acid was 100%. The upper organic phase sample was taken for chromatographic analysis. There was no 3-hydroxy-3-(3-pyridine) acrylic acid residue in the upper organic phase, and the organic phase was emptied. 400 g of 98% concentrated sulfuric acid was added, heated to 130 ° C for reaction for 120 min, returned to room temperature, adjusted the pH value to neutral, and a large amount of white solid was precipitated. After filtration, drying and weighing, the yield was 85.9%, the product chromatographic purity was 100%, and the nuclear magnetic resonance hydrogen spectrum characterized the correct synthesis of the molecule.

[0039] Example 2

[0040] The specific reaction process is similar to that of Example 1. In the first step of the Aldol condensation reaction, after the addition of 3-pyridinealdehyde is completed, the reaction temperature is controlled to -60°C for 15 minutes. After returning to room temperature, 400 ml of saturated sodium sulfate solution is added to quench, stirred for 15 minutes, and the liquid in the kettle is separated into upper and lower layers. The lower aqueous phase is discharged, and a sample of the upper organic phase is taken for chromatographic analysis. The purity of the product tert-butyl 3-hydroxy-3-(3-pyridine)acrylate is 78.1%, and it contains unknown impurities.

[0041] Example 3

[0042] The specific reaction process is similar to that of Example 1. In the first step of the Aldol condensation reaction, after the addition of 3-pyridine aldehyde is completed, the reaction temperature is controlled to -40°C for 15 minutes. After returning to room temperature, 400 ml of saturated sodium sulfate solution is added to quench, stirred for 15 minutes, and the liquid in the kettle is separated into upper and lower layers. The lower aqueous phase is discharged, and a sample of the upper organic phase is taken for chromatographic analysis. The purity of the product tert-butyl 3-hydroxy-3-(3-pyridine)acrylate is 69.3%, and it contains unknown impurities.

[0043] Example 4

[0044] The specific reaction process is similar to that of Example 1. In the first step of the Aldol condensation reaction, the molar ratio of lithium diisopropylamide to tert-butyl acetate is adjusted to 1.2. After the reaction is completed and the temperature is restored to room temperature, 400 ml of saturated sodium sulfate solution is added to quench the reaction, and the mixture is stirred for 15 minutes. The liquid in the kettle is separated into upper and lower layers. The lower aqueous phase is discharged, and a sample of the upper organic phase is taken for chromatographic analysis. The purity of the product tert-butyl 3-hydroxy-3-(3-pyridine)acrylate is 82.7%, and it contains unknown impurities.

[0045] Example 5

[0046] The specific reaction process is similar to that of Example 1. In the first step of the Aldol condensation reaction, the molar ratio of 3-pyridinealdehyde to tert-butyl acetate is adjusted to 0.8. After the reaction is completed and the temperature is restored to room temperature, 400 ml of saturated sodium sulfate solution is added to quench the reaction, and the mixture is stirred for 15 minutes. The liquid in the kettle is separated into upper and lower layers. The lower aqueous phase is discharged, and a sample of the upper organic phase is taken for chromatographic analysis. The purity of the product tert-butyl 3-hydroxy-3-(3-pyridine)acrylate is 89.5%, and it contains possible impurities from the self-condensation of tert-butyl acetate.

[0047] Example 6

[0048] The specific reaction process is similar to that of Example 1. In the second step of the hydrolysis reaction, 400 ml of a 5.0 M LiOH aqueous solution was added at room temperature, stirred at room temperature for 120 min, sulfuric acid was added to neutralize the liquid in the kettle to neutrality, a sample of the lower aqueous phase was taken for chromatographic analysis, and the purity of the product 3-hydroxy-3-(3-pyridine) acrylic acid was 100%, and a sample of the upper organic phase was taken for chromatographic analysis, and no 3-hydroxy-3-(3-pyridine) acrylic acid remained in the upper organic phase.

[0049] Example 7

[0050] The specific reaction process is similar to that of Example 1. In the second step of the hydrolysis reaction, 400 ml of 1.0 M LiOH aqueous solution was added at room temperature, stirred at 40° C. for 120 min, sulfuric acid was added to neutralize the liquid in the kettle to neutrality, and a sample of the lower aqueous phase was taken for chromatographic analysis. The purity of the product 3-hydroxy-3-(3-pyridine) acrylic acid was 100%. A sample of the upper organic phase was taken for chromatographic analysis. A small amount of 3-hydroxy-3-(3-pyridine) acrylic acid remained in the upper organic phase.

[0051] Example 8

[0052] The specific reaction process is similar to that of Example 1. In the third step of dehydration reaction, 200 g of 98% concentrated sulfuric acid was added, heated to 110°C for 120 min, returned to room temperature, and the pH value was adjusted to neutral, and a large amount of white solid was precipitated. After filtration, it was dried and weighed, with a yield of 14.3%.

[0053] Example 9

[0054] The specific reaction process is similar to that of Example 1. In the third step of dehydration reaction, 900 g of 98% concentrated sulfuric acid was added, heated to 130°C for 120 min, returned to room temperature, and the pH value was adjusted to neutral, and a large amount of white solid was precipitated. After filtration, it was dried and weighed, with a yield of 59.2%, a large amount of black oxidized substances were generated on the surface, and the product purity was 62.4%.

[0055] The above are only a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A method for rapidly preparing 3-(3-pyridine)acrylic acid by a one-pot process, characterized in that: The following steps are involved: Tert-butyl acetate is added dropwise to a tetrahydrofuran solution of lithium diisopropylamide, and then 3-pyridinealdehyde is added dropwise, reaction I, quenched with a saturated salt solution, separated, the organic phase is mixed with an alkaline aqueous solution, stirred, reaction II, sulfuric acid is added for neutralization, separated, the organic phase is mixed with an aqueous sulfuric acid solution, reaction III, sodium hydroxide is added for neutralization, precipitated, and filtered to obtain 3-(3-pyridine)acrylic acid.

2. The method according to claim 1, characterized in that: The molar ratio of lithium diisopropylamide to tert-butyl acetate is 1.0 to 1.1; The molar equivalent ratio of 3-pyridinealdehyde to tert-butyl acetate is 0.8 to 1.0; The temperature of the reaction I is -78 to -70°C; The reaction time of the reaction I is 15 to 60 minutes; The temperature of the dropping process does not exceed -70°C.

3. The method according to claim 1, characterized in that The saturated salt solution is selected from at least one of saturated sodium sulfate, saturated sodium chloride, and saturated potassium sulfate.

4. The method according to claim 1, characterized in that: The base is selected from at least one of lithium hydroxide, sodium hydroxide and potassium hydroxide; The concentration of the alkaline aqueous solution is 1 to 5 M; The temperature of the reaction II is 20-30°C; The time of the reaction II is 120 to 240 minutes.

5. The method according to claim 1, characterized in that The concentration of the sulfuric acid aqueous solution is 40-60wt%; The temperature of the reaction III is 120-130°C; The time of the reaction III is 120 to 240 minutes.

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