Method for preventing sodium sand agglomeration in thiophene metallization process

Abstract

The invention discloses a method for preventing sodium sand agglomeration in a thiophene metallization process. The adsorption effect of disodium isopropylbenzene is reduced by properly increasing the proportion of oleic acid; the reaction temperature is strictly controlled, and the temperature is controlled in a lower temperature range in the process of dropwise adding the electron transfer reagent and in the period of continuing the reaction after dropwise adding, so that mutual permeation among sodium particles with low melting points is avoided, and meanwhile, the sodium sand particles are prevented from being adsorbed by the disodium cumene under proper conditions; by strictly adding materials according to the material adding sequence, adding thiophene, tetrahydrofuran and sodium sand at one time, dropwise adding an electron transfer reagent, strictly controlling the dropwise adding speed of the electron transfer reagent, slowly dropwise adding, and properly prolonging the dropwise adding time of alpha-methylstyrene, the generation of a large amount of disodium cumene caused by excessive reactants of the electron transfer reagent is avoided. According to the operation of the method, the liquid does not turn red in the whole process, and sodium sand particles continuously and uniformly become small and finally become flocculent insoluble substances; the method effectively solves the problem of sodium sand agglomeration.

Description

Technical Field

[0001] The present invention relates to the technical field of preparation of thiophene and its derivatives, and in particular to a method for preventing sodium sand from agglomerating during the thiophene metallization process. Background Art

[0002] 2-Thiopheneethanol can be used in the synthesis of various pharmaceuticals. It is a key intermediate in the preparation of [3,2-c]thienopyridine compounds and a precursor to several new drugs for cardiovascular diseases related to platelets and thrombosis, as well as for anti-inflammatory and analgesic purposes. With the continued development of its downstream products, the prospects for 2-thiopheneethanol will be even broader.

[0003] There are many processes for synthesizing 2-thiopheneethanol. Currently, the sodium reagent process is the shortest and lowest-cost process. The first step of this process is thiophene metalation, which is the most critical step in the entire process. During this reaction, sodium sand agglomeration often occurs to varying degrees. The main manifestations are: during the thiophene metalation reaction, the sodium sand particles become coarser, some are scaly, some are flocculent, etc.; after the metalation reaction is completed, larger sodium particles can be seen. In severe cases, the sound of metal hitting the wall can be heard.

[0004] The occurrence of sodium sand agglomeration will cause the following adverse effects: First, it will reduce the utilization rate of sodium and prolong the reaction time. The main reason is that the sodium sand agglomerates, individual particles become coarse, and the reaction rate between large particles and electron transfer reagents is greatly slowed down. After the reaction is completed, the large sodium particles cannot react completely, resulting in a decrease in yield; second, the agglomerated sodium particles react with water during the hydrolysis and acidification stages, releasing hydrogen, which poses a safety risk.

[0005] In the sodium reagent process, sodium sand agglomeration often occurs to varying degrees during the thiophene metallization process, which not only reduces the utilization rate of sodium and increases the cost, but also poses a safety risk.

[0006] Therefore, it is urgent to develop a new synthesis method. Summary of the Invention

[0007] In view of the fact that sodium sand agglomeration often occurs to varying degrees in the sodium reagent process during the thiophene metallization process in the prior art, which not only reduces the utilization rate of sodium and increases the cost, but also poses safety risks, the present application proposes a method for preventing sodium sand agglomeration during the thiophene metallization process.

[0008] To achieve the purpose of the invention, the present invention provides the following technical solutions:

[0009] A method for preventing sodium sand from agglomerating during a thiophene metallization process, comprising the following steps:

[0010] Step S1. Place metallic sodium into a four-necked flask, add xylene and a surfactant in sequence, slowly heat until the sodium is completely melted, and then stir for 15 minutes to produce sodium sand.

[0011] Step S2. After the sodium sand particle size is qualified, stop heating and start cooling to below 20°C;

[0012] Step S3. Add thiophene and tetrahydrofuran to the sodium sand, cool to -2-2°C, and add the electron transfer reagent dropwise at a rate of 6-10 drops / min for 3-5 hours. During the addition, maintain and control the addition rate and observe the liquid color to ensure that the liquid does not turn red. If the liquid turns slightly red, pause the addition for 5-15 minutes. After the red color disappears, continue adding at the predetermined rate.

[0013] Step S4: After the electron transfer reagent is added dropwise, the reaction is continued at 0-3°C for 3-6 hours until all the sodium sand is converted.

[0014] Preferably, in step S1, the surfactant is oleic acid.

[0015] Preferably, in step S1, the ratio of metallic sodium, xylene and oleic acid is 1 mol:100 ml:(0.8-1.5 g).

[0016] Preferably, in step S1, the heating rate is controlled to be 3-5°C / min.

[0017] Preferably, in step S1, the stirring speed is controlled to be 2000-2500 rpm.

[0018] Preferably, the electron transfer reagent in step S3 and step S4 is α-methylstyrene.

[0019] Preferably, the molar ratio of metallic sodium, thiophene and tetrahydrofuran in step S1 and step S3 is 1:(1.4-1.7):(5-7).

[0020] Preferably, the qualified particle size of the sodium sand in step S2 is controlled to be 30-50 μm.

[0021] Preferably, in step S1 and step S3, the ratio of metallic sodium to α-methylstyrene is 1 mol: (0.6-1.0 mol).

[0022] Compared with the existing technology, the technical solution of this application has the following beneficial effects:

[0023] 1. This application has conducted an in-depth analysis of the mechanism of sodium sand agglomeration during the thiophene metallization process. There are two main reasons: first, sodium has a low melting point, and the particles penetrate each other and form metallic bonds at a fast rate, which is a key internal cause of sodium sand agglomeration; second, the electron transfer reagent (α-methylstyrene) itself participates in the chemical reaction to generate isopropylbenzene disodium; isopropylbenzene disodium has a surfactant effect, and isopropylbenzene disodium simultaneously adsorbs two sodium sand particles under suitable conditions. This bridging effect is a key external cause of sodium sand agglomeration. These two reasons work together to promote the agglomeration of sodium sand particles when conditions are suitable. The method used in this application reduces the adsorption of disodium cumene by appropriately increasing the ratio of oleic acid or other surfactants. The reaction temperature is strictly controlled, and the temperature is controlled within a relatively low range during the addition of the electron transfer reagent (α-methylstyrene) and during the continued reaction after the addition is completed, thereby avoiding mutual penetration between sodium particles with low melting points and preventing disodium cumene from adsorbing sodium sand particles under suitable conditions. The materials are added in strict accordance with the order of addition, thiophene, tetrahydrofuran, and sodium sand are added at one time, and the electron transfer reagent is added dropwise. The electron transfer reagent addition speed is strictly controlled, and the addition is slow. The α-methylstyrene addition time is appropriately extended to avoid excessive electron transfer reagent (α-methylstyrene) reactants leading to the large-scale generation of disodium cumene. According to the above method, during the whole process, the liquid does not turn red, the sodium sand particles continue to shrink evenly, and finally become flocculent insoluble matter; this method solves the problem of sodium sand agglomeration, which not only increases the utilization rate of sodium, improves the reaction efficiency, and reduces the reaction time; at the same time, it avoids the reaction of sodium particles with water to release hydrogen, thereby improving production safety. DETAILED DESCRIPTION

[0024] Unless otherwise specified, the reagents and instruments used in the following examples are commercially available conventional products.

[0025] In the following embodiments:

[0026] Example 1:

[0027] A method for preventing sodium sand agglomeration during thiophene metallization, comprising the following steps:

[0028] Step S1, put 1 mol of metallic sodium into a four-necked flask, add 100 ml of xylene and 0.8 g of oleic acid in sequence, slowly heat the flask at a heating rate of 3°C / min until the sodium is completely melted, start stirring, control the stirring rate to 2000-2500 rpm, and stir for 15 minutes to prepare sodium sand;

[0029] Step S2: After the sodium sand particle size reaches 30-50 μm, stop heating and start cooling to below 20°C;

[0030] Step S3: Add 1.4 mol of thiophene and 5 mol of tetrahydrofuran to the sodium sand at once, cool the mixture to 0°C, and then add 0.6 mol of α-methylstyrene dropwise at a rate of 6-10 drops / min for 3 hours. During the addition process, maintain and control the addition rate, observe the color of the liquid, and ensure that the liquid does not turn red. If the liquid turns slightly red, pause the addition for 5-15 minutes. After the red color disappears, continue adding at the predetermined rate.

[0031] Step S4: After the electron transfer reagent is added dropwise, the reaction is continued at 0°C for 6 hours until all the sodium sand is converted.

[0032] During the whole process, the liquid does not turn red, and the sodium sand particles continue to shrink uniformly, eventually becoming flocculent insoluble matter. This method solves the problem of sodium sand agglomeration.

[0033] Example 2:

[0034] A method for preventing sodium sand agglomeration during thiophene metallization is different from Example 1 in that the steps are as follows:

[0035] Step S1, put 1 mol of metallic sodium into a four-necked flask, add 100 ml of xylene and 1.5 g of oleic acid in sequence, slowly heat the flask at a heating rate of 3°C / min until the sodium is completely melted, start stirring, control the stirring rate to 2000-2500 rpm, and stir for 15 minutes to prepare sodium sand;

[0036] Step S2: After the sodium sand particle size reaches 30-50 μm, stop heating and start cooling to below 20°C;

[0037] Step S3: Add 1.7 mol of thiophene and 7 mol of tetrahydrofuran to the sodium sand at once, cool the mixture to 2°C, and then add 1.0 mol of α-methylstyrene dropwise at a rate of 6-10 drops / min for 5 hours. During the addition, maintain and control the addition rate, observe the color of the liquid, and ensure that the liquid does not turn red. If the liquid turns slightly red, pause the addition for 5-15 minutes. After the red color disappears, continue adding at the predetermined rate.

[0038] Step S4: After the electron transfer reagent is added dropwise, the reaction is continued at 3°C ​​for 3 h until all the sodium sand is converted.

[0039] During the whole process, the liquid does not turn red, and the sodium sand particles continue to shrink uniformly, eventually becoming flocculent insoluble matter. This method solves the problem of sodium sand agglomeration.

[0040] Example 3:

[0041] A method for preventing sodium sand agglomeration during thiophene metallization is different from Example 1 in that the steps are as follows:

[0042] Step S1: 1 mol of metallic sodium was put into a four-necked flask, and 100 ml of xylene and 1.0 g of oleic acid were added in sequence. The temperature was slowly raised at a heating rate of 3°C / min until the sodium was completely melted. Then, stirring was started at a stirring rate of 2000-2500 rpm and stirred for 15 minutes to prepare sodium sand.

[0043] Step S2: After the sodium sand particle size reaches 30-50 μm, stop heating and start cooling to below 20°C;

[0044] Step S3: Add 1.5 mol of thiophene and 6 mol of tetrahydrofuran to the sodium sand at once, cool the mixture to -2°C, and then add 0.8 mol of α-methylstyrene dropwise at a rate of 6-10 drops / min for 4 hours. During the addition, maintain and control the addition rate, observe the color of the liquid, and ensure that the liquid does not turn red. If the liquid turns slightly red, pause the addition for 5-15 minutes. After the red color disappears, continue adding at the predetermined rate.

[0045] Step S4: After the electron transfer reagent is added dropwise, the reaction is continued at 3° C. for 5 h until all the sodium sand is converted.

[0046] During the whole process, the liquid does not turn red, and the sodium sand particles continue to shrink uniformly, eventually becoming flocculent insoluble matter. This method solves the problem of sodium sand agglomeration.

[0047] Example 4:

[0048] A method for preventing sodium sand agglomeration during thiophene metallization is different from Example 1 in that the steps are as follows:

[0049] Step S1: 1 mol of metallic sodium was put into a four-necked flask, and 100 ml of xylene and 1.2 g of oleic acid were added in sequence. The temperature was slowly raised at a heating rate of 4°C / min until all the sodium was melted. Then, stirring was started at a stirring rate of 2000-2500 rpm and stirred for 15 minutes to prepare sodium sand.

[0050] Step S2: After the sodium sand particle size reaches 30-50 μm, stop heating and start cooling to below 20°C;

[0051] Step S3: Add 1.7 mol of thiophene and 7 mol of tetrahydrofuran to the sodium sand at once, cool the mixture to 2°C, and then add 1.0 mol of α-methylstyrene dropwise at a rate of 6-10 drops / min for 5 hours. During the addition, maintain and control the addition rate, observe the color of the liquid, and ensure that the liquid does not turn red. If the liquid turns slightly red, pause the addition for 5-15 minutes. After the red color disappears, continue adding at the predetermined rate.

[0052] Step S4: After the electron transfer reagent is added dropwise, the reaction is continued at 0°C for 6 hours until all the sodium sand is converted.

[0053] During the whole process, the liquid does not turn red, and the sodium sand particles continue to shrink uniformly, eventually becoming flocculent insoluble matter. This method solves the problem of sodium sand agglomeration.

[0054] Example 5:

[0055] A method for preventing sodium sand agglomeration during thiophene metallization is different from Example 1 in that the steps are as follows:

[0056] Step S1, put 1 mol of metallic sodium into a four-necked flask, add 100 ml of xylene and 1.5 g of oleic acid in sequence, slowly heat the flask at a heating rate of 3°C / min until the sodium is completely melted, start stirring, control the stirring rate to 2000-2500 rpm, and stir for 15 minutes to prepare sodium sand;

[0057] Step S2: After the sodium sand particle size reaches 30-50 μm, stop heating and start cooling to below 20°C;

[0058] Step S3: Add 1.4 mol of thiophene and 5 mol of tetrahydrofuran to the sodium sand at once, cool the mixture to -2°C, and then add 0.7 mol of α-methylstyrene dropwise at a rate of 6-10 drops / min for 3 hours. During the addition, maintain and control the addition rate, observe the color of the liquid, and ensure that the liquid does not turn red. If the liquid turns slightly red, pause the addition for 5-15 minutes. After the red color disappears, continue adding at the predetermined rate.

[0059] Step S4: After the electron transfer reagent is added dropwise, the reaction is continued at 2° C. for 4 h until all the sodium sand is converted.

[0060] During the whole process, the liquid does not turn red, and the sodium sand particles continue to shrink uniformly, eventually becoming flocculent insoluble matter. This method solves the problem of sodium sand agglomeration.

[0061] Example 6:

[0062] A method for preventing sodium sand agglomeration during thiophene metallization is different from Example 1 in that the steps are as follows:

[0063] Step S1: 1 mol of metallic sodium was put into a four-necked flask, and 100 ml of xylene and 1.5 g of oleic acid were added in sequence. The temperature was slowly raised at a heating rate of 5°C / min until the sodium was completely melted. Then, stirring was started at a stirring rate of 2000-2500 rpm and stirred for 15 minutes to prepare sodium sand.

[0064] Step S2: After the sodium sand particle size reaches 30-50 μm, stop heating and start cooling to below 20°C;

[0065] Step S3: Add 1.7 mol of thiophene and 7 mol of tetrahydrofuran to the sodium sand at once, cool the mixture to -2°C, and then add 0.6 mol of α-methylstyrene dropwise at a rate of 6-10 drops / min for 5 hours. During the addition, maintain and control the addition rate, observe the color of the liquid, and ensure that the liquid does not turn red. If the liquid turns slightly red, pause the addition for 5-15 minutes. Once the red color disappears, continue adding at the prescribed rate.

[0066] Step S4: After the electron transfer reagent is added dropwise, the reaction is continued at 0°C for 6 hours until all the sodium sand is converted.

[0067] During the whole process, the liquid does not turn red, and the sodium sand particles continue to shrink uniformly, eventually becoming flocculent insoluble matter. This method solves the problem of sodium sand agglomeration.

[0068] The above description is only a preferred embodiment of the present invention and does not limit the present invention. It should be clear to those skilled in the art that various modifications and changes can be made to the exemplary embodiments of the present invention without departing from the spirit and scope defined by the claims.

Claims

1. A method for preventing sodium sand agglomeration during thiophene metallization, characterized in that: Specifically include the following steps: Step S1. Sodium metal is placed in a four-necked flask, and xylene and a surfactant are added in sequence. The temperature is slowly raised at a rate of 3°C / min until the sodium is completely melted. Stirring is then started at a rate of 2000-2500 rpm for 15 minutes to produce sodium sand. Step S2. After the sodium sand particle size is qualified, stop heating and start cooling to below 20°C; Step S3. Add thiophene and tetrahydrofuran to the sodium sand, cool to -2-2°C, and add the electron transfer reagent dropwise at a rate of 6-10 drops / min for 3-5 hours. During the addition, maintain and control the addition rate and observe the liquid color to ensure that the liquid does not turn red. If the liquid turns slightly red, pause the addition for 5-15 minutes. Once the red color disappears, continue adding at the prescribed rate. Step S4: After the electron transfer reagent is added dropwise, the reaction is continued at 0-3°C for 3-6 hours until all the sodium sand is converted.

2. The method for preventing sodium sand agglomeration during thiophene metallization according to claim 1, characterized in that: In the step S1, the surfactant is oleic acid.

3. The method for preventing sodium sand agglomeration during thiophene metallization according to claim 2, characterized in that: In step S1, the ratio of metallic sodium, xylene and oleic acid is 1 mol: 100 ml: (0.8-1.5 g).

4. The method for preventing sodium sand agglomeration during thiophene metallization according to claim 1, characterized in that: In step S1, the heating rate is controlled to be 3-5°C / min.

5. The method for preventing sodium sand agglomeration during thiophene metallization according to claim 1, characterized in that: In step S1, the stirring speed is controlled to be 2000-2500 rpm.

6. The method for preventing sodium sand agglomeration during thiophene metallization according to claim 1, characterized in that: The electron transfer reagent in step S3 and step S4 is α-methylstyrene.

7. The method for preventing sodium sand agglomeration during thiophene metallization according to claim 1, characterized in that: The molar ratio of metallic sodium, thiophene and tetrahydrofuran in step S1 and step S3 is 1:(1.4-1.7):(5-7).

8. The method for preventing sodium sand agglomeration during thiophene metallization according to claim 6, characterized in that: In the steps S1 and S3, the ratio of the metallic sodium to α-methylstyrene is 1 mol: (0.6-1.0 mol).

9. The method for preventing sodium sand agglomeration during thiophene metallization according to claim 1, characterized in that: In step S2, the qualified particle size of the sodium sand is controlled to be 30-50 μm.