A process for the synthesis of p-ethylpropiophenone intermediates based on continuous flow devices

Abstract

The application provides a synthesis process of p-ethylbenzalacetone intermediate based on a continuous flow device. First, a solution A is prepared by mixing a Lewis acid, propionyl chloride and a solvent according to a certain equivalent ratio, then a solution B is prepared by mixing ethylbenzene and a solvent according to a certain equivalent number, and then p-ethylbenzalacetone is prepared by using a continuous flow device. The continuous flow device has the advantages of large specific surface area, high yield, high stability, high selectivity, low energy consumption, short contact time, few by-products, rapid amplification and the like. Compared with a traditional kettle reaction, the application does not need to heat the whole kettle body, consumes less energy, and has less reaction liquid in unit time, is safer, and has high repeatability. The p-ethylbenzalacetone prepared by using the continuous flow device provided by the application has a purity of more than 98% and a yield of more than 95%.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and relates to a method for preparing a pharmaceutical intermediate, and more particularly to a synthesis process for p-ethylphenylacetone intermediate based on a continuous flow device. Background Technology

[0002] p-Ethylphenylacetone has the molecular formula C11H14O and a molecular weight of 162.23. It is a pale yellow or colorless liquid with the molecular formula shown in formula (Ⅰ). It is mainly used in organic synthesis and as an intermediate in the synthesis of corresponding drugs. For example, p-Ethylphenylacetone is a drug intermediate for the preparation of etorizine hydrochloride for the prevention and treatment of cardiovascular and cerebrovascular diseases. It is also a key intermediate for the preparation of astemizole, a drug used to treat perennial and seasonal allergic rhinitis, allergic conjunctivitis, chronic urticaria and other allergic reaction symptoms and signs.

[0003]

[0004] Current technologies for synthesizing ethyl phenylacetone mostly employ batch reactors, using dropwise feeding to control the significant exothermic reaction and maintain the reaction temperature within a suitable range. Furthermore, the yield is limited by the reactor volume. If an operational error occurs, the entire batch of material may be wasted and cannot be recovered. Additionally, existing synthesis processes have a low yield of approximately 85%. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a new synthesis process for p-ethyl acetone intermediates in order to address the shortcomings of the prior art. This process is based on a continuous flow device to improve production efficiency, produce high-purity products, achieve continuous production, and is safer. It is suitable for large-scale industrial production and requires less floor space.

[0006] The present invention provides a synthesis process for p-ethylphenylacetone intermediate based on a continuous flow device, comprising the following steps:

[0007] Step 1: Mix 1-3 eq Lewis acid and 1-1.5 eq propionyl chloride in 3-10V dichloromethane to form solution A;

[0008] Step 2: Take 1 eq of phenylethyl and mix it in 3-10V dichloromethane to form solution B;

[0009] Step 3: Prepare p-ethylacetone using a continuous flow reactor.

[0010] The continuous flow reactor for step three includes the following components:

[0011] Glass storage tank A, glass storage tank B, and glass storage tank C; glass storage tank A is used to store solution A described in step one, glass storage tank B is used to store solution B described in step two, and glass storage tank C is used to collect the p-ethylphenylacetone reaction solution prepared in step three.

[0012] Precooling tube A and precooling tube B; precooling tube A is used to cool solution A from glass storage tank A, and precooling tube B is used to cool solution B from glass storage tank B;

[0013] A first flow pump and a second flow pump; the solution A stored in the glass storage tank A is pumped into the precooling pipe A via the first flow pump; the solution B stored in the glass storage tank B is pumped into the precooling pipe B via the second flow pump;

[0014] Reaction tube; pre-cooled solutions A and B are simultaneously introduced into the reaction tube and mixed, and the reaction is carried out in the reaction tube to prepare p-ethylacetone reaction solution;

[0015] After the reaction is carried out in the reaction tube, the product p-ethyl acetone reaction solution is collected in glass storage tank C.

[0016] The components are connected by polytetrafluoroethylene pipes;

[0017] The precooling pipe A, precooling pipe B, and reaction pipe are placed in the bath of the integrated hot and cold circulation machine.

[0018] Preferably, the continuous flow reaction device is as follows: Figure 1 The continuous flow reaction apparatus shown.

[0019] Preferably, the precooling pipe A and the precooling pipe B have a length of 2 meters.

[0020] Preferably, the reaction tube is 15 to 20 meters long. Further, the temperature inside the reaction tube is set at -40±2℃.

[0021] Preferably, the temperature inside the bath of the integrated hot and cold circulation machine is controlled at -40 to 40°C, more preferably -40°C, and the solution inside the bath is ethanol.

[0022] Preferably, when the flow rate of the first flow pump is increased by 1 to 5 units based on the flow rate of the second flow pump, the yield and purity can reach a high level. More preferably, the flow rates are: first flow pump (21 ml / min) and second flow pump (18 ml / min), or first flow pump (25 ml / min) and second flow pump (20 ml / min), or first flow pump (21 ml / min) and second flow pump (20 ml / min).

[0023] Preferably, nitrogen gas is introduced into the glass storage tank A and the glass storage tank B as a protective gas.

[0024] Preferably, the first flow pump and the second flow pump are selected from peristaltic pumps or plunger pumps.

[0025] Preferably, in some embodiments of the present invention, in step one, the volumetric mass of the dichloromethane solvent is 5 to 7 times the mass of propionyl chloride; specifically, the volumetric mass of the dichloromethane solvent is 5, 6, or 7 times the mass of propionyl chloride. The applicant has found through research that if the volumetric mass of the dichloromethane solvent is less than 5 times the mass of propionyl chloride, the reaction efficiency is too low, with a yield of only 34% and a purity of only 65%. However, when the volumetric mass of the added dichloromethane solvent is greater than 7 times the mass of propionyl chloride, it results in unnecessary waste of solvent. Furthermore, due to excessive solvent, reaching the reaction temperature requires more energy, and side reactions occur, reducing the purity of the product.

[0026] Preferably, in some embodiments of the present invention, in step one, the Lewis acid can be selected from one or a mixture of two or three of aluminum trichloride, ferric chloride, and zinc trichloride; further, specifically, the Lewis acid is aluminum trichloride, ferric chloride, zinc trichloride, or a mixture of aluminum trichloride and ferric chloride in a 1:1 ratio; a mixture of aluminum trichloride and zinc trichloride in a 1:2 ratio; a mixture of ferric chloride and aluminum trichloride in a 1:2 ratio; or a mixture of aluminum trichloride, ferric chloride, and zinc trichloride in a 1:1:2 ratio. In step one, under the reaction system of the present invention, the applicant found through experimental research that when using zinc trichloride, the reaction temperature needs to be increased to 35℃~40℃; when the temperature is too low, the reaction cannot proceed quickly, thus prolonging the reaction time, requiring an increase in the reaction tube length or obtaining a crude product with lower purity. Finally, after extensive creative work, the applicant further preferred aluminum trichloride as the Lewis acid to participate in the reaction, achieving a yield and purity of over 90%.

[0027] In some embodiments of the present invention, in step one, the equivalent ratio of Lewis acids is 1.0 to 3.0, specifically, in step one, the equivalent ratio of Lewis acids is 1.0 to 1.5, 1.5 to 2.0, 2.0 to 2.5, or 2.5 to 3.0.

[0028] The applicant discovered through research that when the equivalence ratio of Lewis acids is less than 1.0, the reaction will be incomplete, and when the equivalence ratio of Lewis acids is greater than 3, side reactions will occur, thereby affecting the yield and purity of the final product.

[0029] In some embodiments of the present invention, in step one, the equivalence ratio of propionyl chloride is 1.1 to 1.5, specifically, the equivalence ratio of chloropropane is 1.1 to 1.2, 1.2 to 1.3, 1.3 to 1.4, or 1.4 to 1.5. The applicant has found through research that when the equivalence ratio of propionyl chloride is less than 1.1, the reaction is incomplete; when the equivalence ratio of propionyl chloride is greater than 1.5, side reactions occur, thereby affecting the yield and purity of the final product.

[0030] In some embodiments of the present invention, in step two, the volume of dichloromethane solvent is 3 to 10 times the mass of phenylethyl; specifically, the volume of solvent is 3, 4, 5, 6, 7, 8, 9, or 10 times the mass of phenylethyl. Preferably, it is 3 to 5 times. The applicant has found through research that if the volume of solvent is less than 5 times the mass of phenylethyl, the reaction efficiency is too low; if the volume of solvent is greater than 5 times the mass of phenylethyl, it results in unnecessary waste of solvent, especially when it is greater than 10 times. Furthermore, due to excessive solvent, reaching the reaction temperature requires more energy, leading to a decrease in yield.

[0031] In some embodiments of the present invention, the reaction tube length in the continuous flow apparatus in step three is 5 to 20 meters; specifically, preferably 15 to 20 meters. Furthermore, in specific embodiments, the reaction tube length in the continuous flow apparatus may be determined based on the equivalent amount of substrate added to solution A and solution B, as well as the reaction temperature. The applicant has found through research that if the reaction tube length is less than 5 meters, the reaction is incomplete; if the reaction tube length is greater than 20 meters, it results in unnecessary solvent waste and the generation of byproducts leading to a decrease in purity.

[0032] Compared with the prior art, the present invention has achieved at least the following beneficial effects:

[0033] This invention utilizes a continuous flow apparatus to synthesize the intermediate p-ethylphenylacetone. Continuous flow apparatus offers advantages such as large specific surface area, high yield, high stability, high selectivity, low energy consumption, short contact time, fewer byproducts, and rapid scale-up. Compared to traditional batch reactors, this invention eliminates the need to heat the entire reactor, consumes less energy, and produces less reaction liquid per unit time, resulting in greater safety and high reproducibility. Through extensive experimental work, the applicant discovered that when the mass-volume fraction of dichloromethane in solutions A and B is 3-5, the equivalent number of propionyl chloride is 1.1-1.15, the equivalent number of aluminum trichloride as a Lewis acid is 1.2-1.25, and the reaction tube length is 20 meters, controlling the temperature within the integrated hot and cold circulation bath at -40°C yields an unexpectedly high purity of over 98% and a yield of over 95%. Attached Figure Description

[0034] Figure 1This diagram shows the continuous flow apparatus used in the synthesis of p-ethylphenylacetone according to the present invention; the arrows indicate the direction in which the solution is pushed by the pump, and the solid lines connecting the various components represent that the components are connected by polytetrafluoroethylene pipes. Detailed Implementation

[0035] The present invention will be further described in detail below with reference to embodiments. The description herein is merely illustrative and is not intended to limit the scope of the invention.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention. All reagents and instruments used herein are commercially available, and the characterization methods involved are described in relevant prior art and will not be repeated herein.

[0037] Example 1

[0038] This embodiment describes a synthesis process for a p-ethylphenylacetone intermediate based on a continuous flow device, which includes the following steps:

[0039] Includes the following steps:

[0040] Step 1: Take 157g (1.25eq) of aluminum trichloride Lewis acid and 100.2g (1.15eq) of propionyl chloride and add them sequentially to 300ml (3V) of dichloromethane. Mix and stir for 30min to obtain solution A;

[0041] Step 2: Take 100g of ethylbenzene (1eq) and mix it with 400ml (4V) of dichloromethane to obtain solution B;

[0042] Step 3: React solutions A and B obtained in Step 1 and Step 2 respectively using a continuous flow reactor to prepare p-ethylbenzophenone.

[0043] The continuous flow reactor in step three includes components and operating modes, such as... Figure 1 :

[0044] Glass storage tank A and glass storage tank B; glass storage tank A is used to store solution A described in step one, and glass storage tank B is used to store solution B described in step two. During the reaction, nitrogen gas is introduced into glass storage tank A and glass storage tank B as a protective gas. Solution A, stored in glass storage tank A, is pumped into precooling tube A via a first flow pump; solution B, stored in glass storage tank B, is pumped into precooling tube B via a second flow pump. The lengths of precooling tubes A and B are 2 meters. The flow rate of the first flow pump is adjusted to 21 mL / min, and the flow rate of the second flow pump is 20 mL / min. After precooling, solutions A and B simultaneously enter a reaction tube for mixing. The reaction tube, 20 meters long, is set at a temperature of -40±2℃. A sampling port is provided between the reaction tube and glass storage tank C. The product, p-ethylphenylacetone reaction solution, is collected in glass storage tank C after the reaction in the reaction tube. Precooling tubes A and B, along with the reaction tube, are placed in a hot and cold circulating bath. The temperature inside the hot and cold circulating bath is controlled at -40℃, and the solution in the bath is ethanol. The components are connected by PTFE pipes; the product yield is 95%, and its purity can reach 99%.

[0045] The experiment was conducted following the same operating steps as in Example 1 (the feed flow rates of the first and second flow pumps were kept constant), except that the experimental parameters were changed. The specific experimental parameters and results are shown in Table 1.

[0046] Table 1

[0047]

[0048]

[0049] Note: The dosage of each material is based on ethylbenzene as 1 eq, referring to the corresponding equivalent ratio dosage. The dosage of dichloromethane is calculated based on the mass-volume number V of ethylbenzene.

[0050] Analysis of the experimental results, as shown in Example 1 and Table 1, reveals that when the mass-volume fraction of dichloromethane in both solutions A and B is 3-5, the equivalent number of propionyl chloride is 1.1-1.15, the equivalent number of aluminum trichloride as a Lewis acid is 1.2-1.25, and the reaction tube length is 20 meters, with the temperature controlled at -40°C in the integrated hot and cold circulation bath, the reaction can achieve unexpected results with a purity of over 98% and a yield of over 95%. In contrast, in Example 3, when the mass-volume fraction of dichloromethane in solution B is 10, the molar concentration of ethylbenzene decreases, leading to a significant reduction in the actual amount of ethylbenzene participating in the reaction. Simultaneously, the equivalent numbers of propionyl chloride and aluminum trichloride are in significant excess, resulting in a final reaction purity of 58% and a yield of 56%. Furthermore, when the mass-volume fraction of dichloromethane in solution A is 2, as in Example 6, the reaction purity and yield also decrease, particularly the yield, which drops to only 34%. The length of the reaction tube also has a significant impact on the experimental results. The applicant found that if the tube is too short, the yield is low, as in Example 7, the yield is only 20%. However, if the reaction tube is too long, the purity of the product is correspondingly reduced. This may be because if the reaction tube is too long, solutions A and B mix for too long, leading to the formation of byproducts. In addition, the applicant unexpectedly discovered that controlling the temperature inside the integrated hot and cold cycle bath also has a very important impact on the experimental results. Excessively high temperatures can also lead to a decrease in product purity and the formation of byproducts.

[0051] Based on Example 1 (with the experimental operation steps and other experimental parameters remaining unchanged), the feed flow rates of the first and second flow pumps were adjusted, and the yield and purity of each example were calculated. The specific experimental parameter settings and experimental results are shown in Table 2.

[0052] Table 2

[0053]

[0054] Analysis of the experimental results, as shown in Table 2, reveals that when the flow rates of both the first and second flow pumps are 10 ml / min or are other integer multiples thereof (or when the difference in their feed flow rates is greater than one), the yield and purity of the reaction decrease, resulting in residual raw materials and consequently low yield and purity. However, when the difference in their feed flow rates is less than one, especially when the flow rate of the first flow pump is increased by 1 to 5 units compared to the flow rate of the second flow pump, the yield and purity can reach a higher level. Preferred flow rates include the first flow pump flow rate (21 ml / min) and the second flow pump flow rate (18 ml / min), or the first flow pump flow rate (25 ml / min) and the second flow pump flow rate (20 ml / min), or the first flow pump flow rate (21 ml / min) and the second flow pump flow rate (20 ml / min).

Claims

1. A synthesis process for p-ethylphenylacetone intermediate based on a continuous flow apparatus, characterized in that, Includes the following steps: Step 1: Mix 1.2–1.25 eq aluminum trichloride and 1.1–1.15 eq propionyl chloride in 4–5 V dichloromethane to form solution A; Step 2: Take 1 eq of ethylbenzene and mix it in 4-5V of dichloromethane to form solution B; Step 3: Prepare a p-ethylacetone reaction solution by using a continuous flow reactor with solution A obtained in Step 1 and solution B obtained in Step 2; The continuous flow reactor for step three includes the following components: Glass storage tank A, glass storage tank B, and glass storage tank C; glass storage tank A is used to store solution A described in step one, glass storage tank B is used to store solution B described in step two, and glass storage tank C is used to collect the p-ethylphenylacetone reaction solution prepared in step three; nitrogen gas is introduced into glass storage tanks A and B as a protective gas. Precooling pipe A and precooling pipe B; precooling pipe A is used to cool solution A from glass storage tank A, and precooling pipe B is used to cool solution B from glass storage tank B; the length of precooling pipe A and precooling pipe B is 2 meters. A first flow pump and a second flow pump; the solution A stored in the glass storage tank A is pumped into the precooling pipe A via the first flow pump; the solution B stored in the glass storage tank B is pumped into the precooling pipe B via the second flow pump; wherein, the flow rate of the first flow pump is 1 to 5 units higher than the flow rate of the second flow pump. A reaction tube; solutions A and B, after pre-cooling, are simultaneously introduced into the reaction tube and mixed. The reaction is carried out in the reaction tube to prepare p-ethylphenylacetone reaction solution; the reaction tube is 20 meters long and the temperature inside the reaction tube is set at -40±2℃. After the reaction is carried out in the reaction tube, the product p-ethyl acetone reaction solution is collected in glass storage tank C. The components are connected by polytetrafluoroethylene pipes; The continuous flow reaction device also includes a hot and cold circulation integrated bath. The precooling pipe A and precooling pipe B, as well as the reaction pipe, are placed in the hot and cold circulation integrated bath. The temperature inside the hot and cold circulation integrated bath is controlled at -40°C, and the solution inside the bath is ethanol.

2. The synthesis process of the p-ethylphenylacetone intermediate according to claim 1, characterized in that, The first flow pump has a flow rate of 21 ml / min and the second flow pump has a flow rate of 18 ml / min; or the first flow pump has a flow rate of 25 ml / min and the second flow pump has a flow rate of 20 ml / min; or the first flow pump has a flow rate of 21 ml / min and the second flow pump has a flow rate of 20 ml / min.

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