Novel synthesis method for synthesizing beta-ethylthio butyraldehyde

Abstract

The invention relates to the field of chemical synthesis, in particular to a novel method for synthesizing beta-ethylthiobutyraldehyde, which comprises the following steps: S1, adding an anhydrous polar aprotic solvent which is dried by a 4A molecular sieve and subjected to nitrogen bubbling for 30 minutes to remove oxygen into a reactor provided with an external circulation cooling system under the conditions that the illumination intensity is less than or equal to 50lux in an amber glass reactor, and reacting for 1-2 hours at the temperature of 20-30 DEG C; the water content of the anhydrous polar aprotic solvent is less than or equal to 0.01%, the oxygen content of the anhydrous polar aprotic solvent is less than 5ppm, tetrahydrofuran, diethyl ether or methyl tert-butyl ether is selected as the solvent, the use amount of the solvent is 4 times of the mass of ethanethiol, ethanethiol with the purity of more than or equal to 99% and crotonaldehyde are added according to the molar ratio of 1: (1.05-1.2), high-purity nitrogen is introduced for replacement three times, the nitrogen micro-positive pressure is maintained in the whole process, and the temperature is controlled to be less than or equal to 10 DEG C through external circulation. According to the method, production can be performed in a low-temperature environment, triethylamine serving as a catalyst is not needed, so that unit consumption is lower, and the synthesized beta-ethylthiobutyraldehyde is more stable, less in decomposition and higher in yield and content due to low synthesis temperature.

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis, and particularly relates to a new method for synthesizing β-ethylthio butyraldehyde. Background Art

[0002] Currently, the main method for synthesizing β-ethylthio butyraldehyde in China uses ethanethiol and triethyl crotonaldehyde as raw materials, and under the action of triethylamine as a catalyst, it is prepared through a high-pressure and high-temperature reaction. This method has some obvious deficiencies. Firstly, the high-pressure and high-temperature reaction conditions require high equipment requirements, increasing production costs and operation difficulties. Secondly, triethylamine as a catalyst not only has a relatively high price, but may also bring some side reactions during the reaction, affecting the purity of the product. In addition, the β-ethylthio butyraldehyde synthesized by this traditional method is prone to decomposition during storage and use, resulting in the yield and content being affected. The existing methods for synthesizing β-ethylthio butyraldehyde in the prior art are difficult to carry out in a low-temperature environment, difficult to reduce the unit consumption, unable to improve the stability of the synthesized β-ethylthio butyraldehyde, and unable to increase the yield and content.

[0003] Therefore, a new method for synthesizing β-ethylthio butyraldehyde is proposed, which can be produced in a low-temperature environment, does not require triethylamine as a catalyst, resulting in lower unit consumption. Since the synthesis temperature is low, the synthesized β-ethylthio butyraldehyde is more stable with less decomposition, and the yield and content are higher. Summary of the Invention

[0004] In order to overcome the problems that the existing methods for synthesizing β-ethylthio butyraldehyde in the prior art are difficult to carry out in a low-temperature environment, difficult to reduce the unit consumption, unable to improve the stability of the synthesized β-ethylthio butyraldehyde, and unable to increase the yield and content, therefore, a new method for synthesizing β-ethylthio butyraldehyde is proposed.

[0005] The technical solution of the present invention is as follows: A new method for synthesizing β-ethylthio butyraldehyde, comprising the following steps:

[0006] S1: Under the condition that the light intensity ≤ 50 lux in an amber glass reactor, add an anhydrous polar aprotic solvent that has been dried by 4A molecular sieve and deoxygenated by nitrogen bubbling for 30 minutes to a reactor equipped with an external circulation cooling system. The water content of the anhydrous polar aprotic solvent is ≤ 0.01%, the oxygen content is < 5 ppm, the solvent is selected from tetrahydrofuran, ether or methyl tert-butyl ether, and the dosage is 4 times the mass of ethanethiol. Add ethanethiol with a purity ≥ 99% and crotonaldehyde in a molar ratio of 1:1.05 - 1.2, displace with high-purity nitrogen 3 times, maintain a slightly positive nitrogen pressure throughout the process, and control the temperature ≤ 10 °C through external circulation;

[0007] S2: Add the nitrogen-containing organic base to the reaction solution first, stir under nitrogen sealing at 200 - 300 rpm for 5 minutes; then slowly dropwise add boron trifluoride ether complex under nitrogen protection. The molar ratio of boron trifluoride ether complex to the nitrogen-containing organic base is 1:0.8 - 1.2, and the temperature is controlled at ≤10°C throughout the dropping process;

[0008] S3: Maintain the system temperature at 0 - 10°C, stir the reaction under nitrogen sealing for 3.5 - 4 hours, sample with a nitrogen-sealed gastight syringe for TLC monitoring (developing agent: ethyl acetate / n-hexane = 1:15, v / v; confirm the product Rf = 0.3 ± 0.05 with the reference substance), and quantify by GC internal standard method. Terminate the reaction when the Rf of the crotonaldehyde spot ≈ 0.7 disappears and the area ratio of the product is ≥98%;

[0009] S4: After the reaction is completed, add 7% sodium bicarbonate solution in three equal amounts under nitrogen sealing. The total addition amount is 1.2 times the amount of acid. Add it slowly each time and manually release the gas. After adjusting the pH to 8 - 9, add 0.5% isobutanol to break the emulsion. After liquid separation, wash the organic phase with 5% sodium chloride solution until neutral and then with saturated brine. Add 4A molecular sieve and anhydrous sodium sulfate, dry under nitrogen sealing for 8 hours, filter under nitrogen sealing with a 100-mesh stainless steel sieve, and perform gradient vacuum distillation to collect the fraction with a purity ≥99.5%; when a purity of ≥99.9% is required, purify through a molecularly imprinted column. The sample loading concentration of the molecularly imprinted column is ≤50 mg / mL, and the flow rate is 1.0 mL / min.

[0010] Preferably, the polar aprotic solvent is tetrahydrofuran, ether or methyl tert-butyl ether, and the amount of the polar aprotic solvent used is 4 times the mass of ethanethiol.

[0011] Preferably, the molar ratio of ethanethiol to crotonaldehyde is 1:1.1, the nitrogen-containing organic base is 6% of the amount of pyridine used, and the molar ratio of boron trifluoride ether to pyridine is 1:1.

[0012] Preferably, the reactor is equipped with an external circulation cooling system (temperature control accuracy ±1°C), and the nitrogen protection gas flow rate is constantly 0.5 L / min.

[0013] Preferably, a reference substance solution is used during TLC monitoring, and the formation of the product is confirmed by the Rf value (0.3 ± 0.05).

[0014] Preferably, a 100-mesh stainless steel sieve is used for filtration after drying.

[0015] Preferably, 0.5% (v / v) isobutanol is added to break the emulsion before liquid separation after neutralization.

[0016] Preferably, during purification with the molecularly imprinted column, the sample loading solution concentration is ≤50 mg / mL, the flow rate is controlled at 1.0 mL / min, and the main peak fraction is collected.

[0017] Preferably, the whole reaction process is carried out under low temperature conditions of 0 to 15 °C.

[0018] Advantages of the present invention:

[0019] 1. Through the innovation of the low-temperature catalytic system and the full-process inerting control, the present invention systematically solves the core problems of high pressure and high temperature, catalyst defects and product instability in the traditional synthesis of β-ethylthio butyraldehyde. By using piperidine / pyridine and boron trifluoride etherate as a synergistic catalyst, the double bond of crotonaldehyde is activated under the conditions of 0 to 10 °C and normal pressure, optimizing the molar ratio of ethanethiol to crotonaldehyde to 1:1.1, improving the conversion rate of crotonaldehyde and reducing the unit consumption.

[0020] 2. The amber reactor, slightly positive nitrogen pressure and external circulation temperature control inhibit side reactions, improve the product purity. The post-treatment is carried out by demulsification with isobutanol, gradient distillation and purification by molecular imprinting column, and the yield is increased to ≥92%, and the purity is further improved.

[0021] 3. Triethylamine is not required throughout the reaction process, effectively reducing the solid waste and equipment costs, achieving the green synthesis goal of "low temperature, low consumption, high stability and high purity", and solving the problems in the prior art that the synthesis method of β-ethylthio butyraldehyde is difficult to carry out in a low-temperature environment, difficult to reduce the unit consumption, unable to improve the stability of the synthesized β-ethylthio butyraldehyde, and unable to improve the yield and content. Detailed implementation manners

[0022] The present invention will be further described below in conjunction with embodiments.

[0023] Embodiment 1: The present invention provides an embodiment: a new synthesis method of β-ethylthio butyraldehyde, comprising the following steps:

[0024] S1: In an amber glass reactor under the condition of light intensity ≤ 50 lux, an anhydrous polar aprotic solvent that has been dried by 4A molecular sieve and deoxygenated by nitrogen bubbling for 30 minutes is added to the reactor equipped with an external circulation cooling system. The water content of the anhydrous polar aprotic solvent is ≤ 0.01%, the oxygen content is < 5 ppm, and the solvent is selected from tetrahydrofuran, ether or methyl tert-butyl ether, and the amount used is 4 times the mass of ethanethiol. Ethanethiol with a purity ≥ 99% and crotonaldehyde are added in a molar ratio of 1:1.05 to 1.2, and replaced with high-purity nitrogen 3 times. The whole process maintains a slightly positive nitrogen pressure, and the temperature is controlled ≤ 10 °C through external circulation.

[0025] S2: First, a nitrogen-containing organic base is added to the reaction solution, and stirred under nitrogen seal at 200 - 300 rpm for 5 minutes; then boron trifluoride etherate complex is slowly added dropwise under nitrogen protection. The molar ratio of boron trifluoride etherate complex to the nitrogen-containing organic base is 1:0.8 to 1.2, and the temperature is controlled ≤ 10 °C during the whole dropping process.

[0026] S3: Maintain the system temperature at 0 - 10°C, stir the reaction under nitrogen sealing for 3.5 - 4 hours, take samples with a nitrogen-sealed airtight needle for TLC monitoring (developing agent: ethyl acetate / n-hexane = 1:15, v / v; confirm the product Rf = 0.3 ± 0.05 with the reference substance), and quantify by internal standard method of GC. Terminate the reaction when the Rf of crotonaldehyde spot ≈ 0.7 disappears and the area ratio of the product ≥ 98%;

[0027] S4: After the reaction is completed, add 7% sodium bicarbonate solution in three equal amounts under nitrogen sealing, and the total addition amount is 1.2 times the amount of acid. Add it slowly each time and manually release the gas. After adjusting the pH to 8 - 9, add 0.5% isobutanol to break the emulsion. After liquid separation, wash the organic phase with 5% sodium chloride solution until neutral and then with saturated brine. Add 4A molecular sieve and anhydrous sodium sulfate, dry under nitrogen sealing for 8 hours, filter under nitrogen sealing with a 100-mesh stainless steel sieve, and distill under gradient reduced pressure to collect the fraction with a purity ≥ 99.5%; when a purity ≥ 99.9% is required, purify through a molecularly imprinted column. The sample loading concentration of the molecularly imprinted column ≤ 50 mg / mL, and the flow rate is 1.0 mL / min

[0028] The polar aprotic solvent is tetrahydrofuran, diethyl ether or methyl tert-butyl ether, and the amount of the polar aprotic solvent used is 4 times the mass of ethanethiol.

[0029] The molar ratio of ethanethiol to crotonaldehyde is 1:1.1, the nitrogen-containing organic base is 6% of the amount of pyridine used, and the molar ratio of boron trifluoride diethyl etherate to pyridine is 1:1.

[0030] The reactor is equipped with an external circulation cooling system (temperature control accuracy ±1°C), and the nitrogen protection gas flow rate is constantly 0.5 L / min.

[0031] When performing TLC monitoring, use the reference substance solution to confirm the formation of the product through the Rf value (0.3 ± 0.05).

[0032] For the filtration after drying, use a 100-mesh stainless steel sieve to remove the molecular sieve particles to avoid blockage during distillation.

[0033] Add 0.5% (v / v) isobutanol to break the emulsion before liquid separation after neutralization.

[0034] When purifying through the molecularly imprinted column, the sample loading solution concentration ≤ 50 mg / mL, control the flow rate at 1.0 mL / min, and collect the main peak fraction.

[0035] The whole reaction process is carried out under low temperature conditions of 0 - 15°C, without the high pressure (< 0.1 MPa) and triethylamine catalysts in the traditional process, to avoid high temperature side reactions.

[0036] Example 2: On the basis of Example 1, the present invention provides an example, and the difference from Example 1 is that:

[0037] Polar aprotic solvent: Diethyl ether (water content ≤ 0.01%, dried over 4A molecular sieves and deoxygenated by nitrogen bubbling) was selected, and the dosage was still 4 times the mass of ethanethiol.

[0038] Reaction temperature control: Since the boiling point of diethyl ether is relatively low (34.6 °C), the temperature control range of the external circulation cooling system was adjusted to -5 to 5 °C (≤ 5 °C throughout the process) to avoid solvent volatilization loss.

[0039] Post-treatment for demulsification: 0.3% (v / v) n-butanol was added before neutralization and liquid separation to break the emulsion, and the density difference between diethyl ether and water (0.71 vs 1.0) was utilized to accelerate the layering.

[0040] Distillation parameters: The initial pressure of gradient vacuum distillation was reduced to -0.095 MPa, the fraction collection temperature was advanced to 35 - 38 °C, and the yield was ≥ 93%.

[0041] Example 3: On the basis of Example 1, the present invention provides an example, which is different from Example 1 in that: nitrogen-containing organic base: piperidine was selected, and the dosage was 5% of the molar amount of ethanethiol. Since piperidine has stronger basicity (pKa = 11.2, pyridine pKa = 5.2), the activation time was shortened to 3 minutes.

[0042] Ratio of boron trifluoride diethyl ether complex: The molar ratio to piperidine was adjusted to 1:0.8. The high coordination ability of piperidine was utilized to reduce the catalyst dosage and the burden of acid neutralization in post-treatment.

[0043] Reaction time: Since piperidine has higher catalytic activity, the stirring reaction time was shortened to 3 hours. TLC monitoring showed that the crotonaldehyde spot (Rf = 0.7) disappeared in 2.5 hours, and the product purity determined by GC internal standard method was ≥ 98.2%.

[0044] Drying and filtration: Dried with 3A molecular sieves and anhydrous sodium sulfate (1:2). Since piperidine residues are easily adsorbed by 4A molecular sieves, 3A molecular sieves selectively retain water to reduce product loss. The GC water content in the filtrate after drying was < 0.005%.

Claims

1. A new method for synthesizing β-ethylthio butyraldehyde, characterized in that, It includes the following steps: S1: Under the condition that the light intensity ≤ 50 lux in an amber glass reactor, add an anhydrous polar aprotic solvent that has been dried by 4A molecular sieve and deoxygenated by nitrogen bubbling for 30 minutes into the reactor equipped with an external circulation cooling system. The water content of the anhydrous polar aprotic solvent is ≤ 0.01%, the oxygen content is < 5 ppm. The solvent is selected from tetrahydrofuran, ether or methyl tert-butyl ether, and the dosage is 4 times the mass of ethanethiol. Add ethanethiol with a purity ≥ 99% and crotonaldehyde in a molar ratio of 1:1.05 - 1.2, displace with high-purity nitrogen 3 times, maintain a slightly positive nitrogen pressure throughout the process, and control the temperature ≤ 10 °C through external circulation; S2: First add a nitrogen-containing organic base to the reaction solution, stir under nitrogen seal at 200 - 300 rpm for 5 minutes; then slowly add boron trifluoride diethyl ether complex dropwise under nitrogen protection. The molar ratio of boron trifluoride diethyl ether complex to the nitrogen-containing organic base is 1:0.8 - 1.2, and control the temperature ≤ 10 °C during the whole dropping process; S3: Maintain the system temperature at 0 - 10 °C, stir and react under nitrogen seal for 3.5 - 4 hours. Use a nitrogen-sealed airtight syringe to sample for TLC monitoring (developing agent: ethyl acetate / n-hexane = 1:15, v / v; confirm the product Rf = 0.3 ± 0.05 with the reference substance), and quantitatively analyze by GC internal standard method. When the Rf of the crotonaldehyde spot ≈ 0.7 disappears and the area ratio of the product is ≥ 98%, terminate the reaction; S4: After the reaction is completed, add 7% sodium bicarbonate solution in 3 equal amounts under nitrogen seal. The total addition amount is 1.2 times the amount of acid. Add slowly each time and manually release gas. After adjusting the pH to 8 - 9, add 0.5% isobutanol to break the emulsion. After liquid separation, wash the organic phase with 5% sodium chloride solution until neutral and then with saturated brine, add 4A molecular sieve and anhydrous sodium sulfate, dry under nitrogen seal for 8 hours, filter under nitrogen seal through a 100-mesh stainless steel sieve, and distill under gradient reduced pressure to collect fractions with a purity ≥ 99.5%; when a purity ≥ 99.9% is required, purify through a molecularly imprinted column. The loading concentration of the molecularly imprinted column is ≤ 50 mg / mL, and the flow rate is 1.0 mL / min.

2. A novel synthetic method of β-ethylthio butyraldehyde according to claim 1, characterized in that: The polar aprotic solvent is tetrahydrofuran, ether or methyl tert-butyl ether, and the dosage of the polar aprotic solvent is 4 times the mass of ethanethiol.

3. A novel synthetic method of β-ethylthio butyraldehyde according to claim 1, characterized in that: The molar ratio of ethanethiol to crotonaldehyde is 1:1.1, the nitrogen-containing organic base is 6% of the dosage of pyridine, and the molar ratio of boron trifluoride diethyl ether to pyridine is 1:

1.

4. A novel synthetic method of β-ethylthio butyraldehyde according to claim 1, characterized in that: The reactor is equipped with an external circulation cooling system (temperature control accuracy ± 1 °C), and the nitrogen protection gas flow rate is constantly 0.5 L / min.

5. A new synthetic method for synthesizing β-ethylthio butyraldehyde according to claim 1, characterized in that: Use a reference substance solution during TLC monitoring, and confirm the formation of the product through the Rf value (0.3 ± 0.05).

6. A novel synthetic method of β-ethylthio butyraldehyde according to claim 1, characterized in that: Use a 100-mesh stainless steel sieve for filtration after drying.

7. A novel synthetic method for β-ethylthio butyraldehyde according to claim 1, characterized in that: Add 0.5% (v / v) isobutanol to break the emulsion before liquid separation after neutralization.

8. A novel synthetic method for β-ethylthio butyraldehyde according to claim 1, characterized in that: During purification through the molecularly imprinted column, the loading solution concentration is ≤ 50 mg / mL, the flow rate is controlled at 1.0 mL / min, and collect the main peak fractions.

9. A novel synthetic method of β-ethylthio butyraldehyde according to claim 1, characterized in that: The whole reaction process is carried out under low temperature conditions of 0 - 15 °C.