Preparation process and device of 2, 5-dibromo adipic acid diester

Abstract

The invention belongs to the field of organic synthesis, and particularly discloses a novel process and device for efficiently preparing 2, 5-dibromo-adipic acid diester, and the process realizes accurate synthesis of a target product through four key steps of acylating chlorination, bromination, esterification and post-treatment. Particularly, in the bromination step, a tubular reaction device heated by a tetrafluoro coil pipe is innovatively adopted, and catalyst particles prepared by mixing red phosphorus, silica gel and a molecular sieve are filled, so that the bromination reaction efficiency is remarkably improved, and the loss of bromine is reduced. Besides, the invention further designs a special preparation device which comprises a reaction kettle, a tubular reaction device and an esterification reaction kettle and is matched with a peristaltic pump and a high-temperature circulating oil bath device, so that automation and high efficiency of the whole preparation process are realized. According to the method, the yield and the purity of the 2, 5-dibromo-adipic acid diester are improved, the production cost is reduced, and a new technical solution is provided for industrial production in related fields.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically discloses a new process and device for efficiently preparing 2,5-dibromoadipate diester. Background Art

[0002] 2,5-dibromoadipate diester is an important chemical intermediate. The commonly used ones are dimethyl ester and diethyl ester. It can be dissolved in organic solvents such as aromatics, hydrocarbons and hydrocarbon derivatives. It is also a commonly used raw material for organic synthesis. In terms of chemical structure, 2,5-dibromoadipate diester has two independent functional groups, two -Br (bromine atoms) and two -COOEt (ester groups). The presence of these functional groups makes 2,5-dibromoadipate diester have many possible variations in chemical reactions. In addition, there are intramolecular hydrogen bonds in the molecular structure of 2,5-dibromoadipate diester, which further improves the stability of its structure. In the application process of 2,5-dibromoadipate diester, its reaction activity is high. It can react with alcohols, phenols, amines and other substances under certain conditions to generate corresponding salts or esters. At the same time, it can also react with active metals such as sodium and potassium to generate corresponding salts. It can be used as a key synthetic intermediate for a variety of drugs.

[0003] As early as 1909, there was a literature report on the synthesis method of 2,5-dibromoadipate diester: adipic acid and thionyl chloride are reacted to generate adipoyl chloride, which is then reacted with bromine to obtain dibromoadipate chloride, and finally esterified with ethanol to obtain 2,5-dibromoadipate diester. Since the target product exists in two forms, meso and racemic, and monobrominated products are also generated, the yield is only 28%. In the face of the problem of low yield in the bromination process, some people subsequently developed a method of catalyzing with solar lamp irradiation (US4736059) to increase the bromination reaction temperature (CN

[0004] 200610122700) method to improve the yield. The present invention team found that the boiling point of bromine was low when repeating the reaction process. In the bromination process, the high temperature caused the loss of bromine to be too large. Although the amount of bromine was increased to 2.6eq, the reaction was still not complete. At the same time, the excessive use of bromine not only had a low utilization rate but also brought great inconvenience to subsequent operations. It was found that the content of the target substance in the reaction solution was only 50%. Considering that the market usage of 2,5-dibromohexanedioic acid diester is large, it is very necessary to further improve its preparation process and find a simple and easy synthesis method with high yield. Summary of the invention

[0005] To solve the above problems, the inventors tried a route of directly brominating and then esterifying adipic acid without going through the chlorination step, as shown in the upper path in the following reaction formula:

[0006]

[0007] In the bromination step, red phosphorus, toluenesulfonic acid and phosphorus tribromide are used as catalysts respectively to obtain 2,5-dibromoadipic acid with a relatively low yield, which is then added to methanol / ethanol for esterification with a total yield of 20%-30%. Although the introduction of the catalyst is helpful for bromination, it needs to be filtered out, which brings instability to the operation and the yield is not ideal. The feasibility of this scheme needs to be further verified, but the inventor has obtained a hint through this route that in order to improve the yield of the bromination reaction, a catalyst needs to be added and the reaction temperature needs to be increased to achieve a better effect. Therefore, the present invention has conducted in-depth research on the following two parts.

[0008] In terms of temperature rise:

[0009] In the process of directly raising the reactor to a higher temperature and then adding bromine, bromine has a low boiling point, resulting in excessive losses, and is easy to leak, which is not conducive to product purification. Based on the continuous flow reaction process that has been popular in recent years, the invention team creatively adopted a tubular reaction method to heat the reaction mixture through a polytetrafluoroethylene coil, which effectively solved the problem.

[0010] In terms of catalyst

[0011] Although the tubular reaction solves the problem of high-temperature heating, it is inconvenient to use the catalyst. In view of this situation, the inventors improved the structure of the tubular reaction device and developed a new type of heat exchange reaction device. The catalyst was processed into particles and placed inside the "heat exchange device" in the form of filler, ultimately achieving the continuous and efficient synthesis of 2,5-dibromoadipate diester.

[0012] To better describe the present invention, the present invention includes the following specific technical solutions:

[0013] A preparation process of 2,5-dibromoadipate diester, characterized by comprising the following steps:

[0014] a. Chlorination step: reacting adipic acid with thionyl chloride in a reactor to obtain adipoyl chloride;

[0015] b. Bromination step: mixing the adipoyl chloride obtained in step a with liquid bromine, and conducting a bromination reaction through a tubular reaction apparatus, wherein the tubular reaction apparatus adopts a tetrafluoroethylene coil heating form to conduct the reaction to reduce the loss of bromine and improve the reaction efficiency;

[0016] c. Esterification step: esterify the product after bromination in step b with anhydrous ethanol in a reactor to obtain diethyl 2,5-dibromoadipate;

[0017] d. Post-treatment step: filtering, beating, drying, etc. the reaction solution obtained in step c to obtain the final product 2,5-dibromoadipate diester.

[0018] Furthermore, in the above-mentioned preparation process of 2,5-dibromoadipate diester, in step b, the tubular reaction device is filled with a granular catalyst, the catalyst is made by mixing red phosphorus, silica gel and molecular sieve, and is placed in the tubular reaction device in the form of a filler to improve the efficiency of the bromination reaction.

[0019] Furthermore, in the above-mentioned preparation process of 2,5-dibromoadipate diester, the preparation method of the catalyst includes: grinding red phosphorus into fine powder and then mixing it evenly with silica gel, adding a suitable concentration of CMC-Na solution to mix it into a viscous paste, and then mixing it evenly with molecular sieves to form spherical catalyst particles, which are then dried and activated.

[0020] Furthermore, in the above-mentioned preparation process of 2,5-dibromoadipate diester, in step b, the tubular reaction device is a heat exchange reaction device, and its main outer barrel and internal straight tubes are both made of glass, and multiple straight tubes are filled with catalyst particles to form a complete passage. The reaction liquid is heated during the flow and a bromination reaction occurs.

[0021] The invention discloses a device for preparing 2,5-dibromoadipate diester, comprising a reaction kettle, a tubular reaction device and an esterification reaction kettle, wherein the tubular reaction device adopts a tetrafluoroethylene coil heating form, is filled with a granular catalyst, the catalyst is mixed with red phosphorus, silica gel and molecular sieve, and is placed in the tubular reaction device in the form of a filler, the reaction kettle is used for acyl chloride reaction, the tubular reaction device is used for bromination reaction, and the esterification reaction kettle is used for esterification reaction.

[0022] Furthermore, in the above-mentioned device for preparing 2,5-dibromoadipate diester, the tubular reaction device is a heat exchange reaction device, and its main outer barrel and internal straight tubes are both made of glass, and multiple straight tubes are filled with catalyst particles to form a complete passage.

[0023] Furthermore, the above-mentioned device for preparing 2,5-dibromoadipate diester also includes a peristaltic pump and a high-temperature circulating oil bath device, wherein the peristaltic pump is used to suck out the mixed liquid in the reaction kettle and pump it into the tubular reaction device, and the high-temperature circulating oil bath device is used to provide heating for the tubular reaction device.

[0024] The invention also discloses a 2,5-dibromoadipate diester, which is prepared by any of the above methods or devices.

[0025] Compared with the prior art, the present invention has the following outstanding beneficial effects:

[0026] Significantly improve the yield: By adopting the tubular continuous reaction principle and creatively improving the device, the preparation process of the present invention greatly improves the yield of 2,5-dibromoadipate diester. In the example where the catalyst was added, the yield reached 55%, which is a significant improvement compared to the 28% yield of the traditional method.

[0027] Reduce the amount of bromine used: The use of tubular reaction devices allows the bromination reaction to be carried out efficiently at high temperatures, thereby significantly reducing the amount of bromine used. This not only reduces production costs, but also reduces the emission of harmful substances, which is of positive significance to environmental protection.

[0028] Simplified operation steps: The preparation process of the present invention effectively integrates the bromination and esterification steps, avoiding cumbersome intermediate separation and purification steps, thereby simplifying the entire preparation process.

[0029] Improve process safety: The use of continuous flow reaction equipment makes the reaction process easier to control and reduces the risk of safety accidents. At the same time, the catalyst is added in the form of particles, avoiding the operation step of filtering and removing, further improving the safety of the process. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The reaction device in Example 1;

[0031] Figure 2 Schematic diagram of the heat exchange reactor structure in Example 2;

[0032] Among them: 1 acyl chloride reactor, 2 peristaltic pump, 3 front section coil, 4 rear section coil, 5 esterification reactor, 6 outer barrel of heat exchange reactor body, 7 straight pipe, 8 polytetrafluoroethylene round plate, 9 outlet, 10 inlet, 11 peristaltic pump inlet, 12 peristaltic pump outlet, 13 polytetrafluoroethylene hose. DETAILED DESCRIPTION

[0033] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] Example 1

[0035] (without catalyst), see Figure 1 .

[0036] The first step (chlorination):

[0037] To a 5L chlorination reactor 1) connected to an alkali tail gas absorber, add 584g (4mol) of adipic acid and 1190g (10mol, 2.5eq) of thionyl chloride, start stirring and set the speed to 300rpm, slowly raise the temperature to 60°C, acidic gas is continuously released and absorbed in the system, and after the solution becomes clear and transparent, continue stirring and reacting for 2h, then the excess thionyl chloride is evaporated under reduced pressure from the rear of the tail gas absorber (connected by a tetrafluoro tube) to obtain adipic acid chloride, which is directly subjected to the next step of reaction without purification.

[0038] Step 2 (Bromination):

[0039] like Figure 1 As shown, the temperature of the acyl chloride reaction kettle 1) in the previous step was lowered to room temperature, and then 1012 g (8.2 mol, 2.05 eq) of liquid bromine dried with concentrated sulfuric acid was added and stirred to mix evenly.

[0040] Take 10m of 6mm*4mm tetrafluoroethylene tube and divide it into two coils (not cut). The front section 3) is about 8m long and is placed in an oil bath. The rear section 4) is about 2m long and is placed in an ice water bath to cool down.

[0041] The mixed liquid in the reactor was sucked out by a peristaltic pump 2 and pumped into the coils (3 and 4). The speed of the pump was set to 1.5 rpm (about 3 ml / min), and the temperature of the oil bath was set to 120°C. It was observed that the liquid in the coils (3 and 4) gradually changed from dark red to light red during the flow. A small amount of dark red liquid seeped out of the hose in the peristaltic pump 2, but it did not affect the reaction.

[0042] Step 3 (esterification):

[0043] The tail of the rear section coil 4) of the previous step is directly introduced into an esterification reactor 5) containing 2000 ml of anhydrous ethanol (dried with molecular sieves) for stirring reaction. The reaction is exothermic and the temperature is controlled not to exceed 30°C. The solution quickly turns red. As the reaction proceeds, white solid can be observed to be gradually generated in the esterification reactor 5. After all the liquid has been transferred through the coils (3 and 4), the stirring reaction is continued for 2 hours.

[0044] Step 4 (post-processing):

[0045] The reaction solution after esterification was allowed to stand overnight, filtered, the filter cake was treated with ethanol pulp, filtered again, and vacuum dried to obtain 420g of white solid target product. The two filtrates were combined, concentrated to half the volume and placed in a -20°C freezer for 2D, frozen for crystallization, filtered, the filter cake was treated with ethanol pulp, filtered again, and vacuum dried to obtain 289g of white solid target product, with a total yield of 54%. After combining the two filtrates and concentrating them, it was found that in addition to a small amount of monobrominated substituted products, there were still a large amount of target products (racemic bodies), and the mother liquor was retained and concentrated for distillation and purification.

[0046] Example 2

[0047] (Adding Catalyst) This embodiment uses a catalyst and a newly designed heat exchange reactor to replace the coils (3 and 4) in Example 1 to overcome the defects encountered in Example 1, such as small reaction scale and pipeline blockage.

[0048] The first step of acyl chloride, the third step of esterification and post-treatment are basically the same as those in Example 1, except that the reaction device is improved during the bromination process. In the bromination stage, a catalyst needs to be added to accelerate the reaction process, but the coil-shaped structure has a thin passage, which is not easy to react in large quantities. At the same time, directly loading the catalyst will cause the pipeline to be blocked, and the state of the catalyst and the size of the pipeline need to be improved accordingly.

[0049] In the first step (acyl chlorination), the reaction conditions are the same as those in Example 1, but the feed amount is doubled.

[0050] Step 2 (Bromination)

[0051] 1. Preparation of catalyst

[0052] Preparation method of the catalyst: Take 50g red phosphorus (ground into fine powder) and 250g silica gel, mix them thoroughly, add an appropriate amount of 0.7% concentration CMC-Na solution, mix into a viscous paste, take another 3000g molecular sieve (diameter 3-5mm) and mix them evenly, put them on a tray to dry at room temperature, and then place them in a 105℃ oven for activation for 0.5h. After sieving out the fine powder, spherical catalyst particles are obtained.

[0053] Design of heat exchange reactor

[0054] like Figure 2 As shown: the outer barrel 6) of the heat exchange reactor body and the 14 straight tubes 7) inside are all made of glass, and two PTFE round plates 8) are used as plugs. The multiple straight tubes 7) are filled with the above-prepared catalyst particles, and the nozzles passing through the PTFE plates 8) are connected in sequence with PTFE hoses 13) to form a complete passage. The two ends of the shell are provided with an inlet 10) and an outlet 9) respectively connected to the inlet and outlet of the high-temperature circulating oil bath. The reaction liquid is pumped in from the port 11) by a peristaltic pump, and flows out from the port 12) and is connected to the esterification reactor 5).

[0055] The mixed liquid in the reactor is sucked out by a peristaltic pump and pumped into the above heat exchange reactor. The pump speed is set to 4rpm (about 8ml / min), and the circulating oil bath temperature is set to 120℃. The reaction liquid is heated and bromination reaction occurs during the process of flowing through the heat exchange reactor. After testing, the catalyst does not need to be replaced after 10 reactions of the same scale.

[0056] The third step (esterification),

[0057] The tail of the heat exchange reactor in the previous step was connected to a PTFE coil and cooled in an ice-water bath, and then introduced into an esterification reactor 5 containing 1000 ml of anhydrous ethanol (dried by molecular sieves) and stirred (connected to a low-temperature circulator) for reaction. The reaction was exothermic and the temperature was controlled not to exceed 30°C. All the liquids were transferred as much as possible (since the "dead volume" of the pipeline was much larger than that of the PTFE coil in Example 1, the reaction liquid could not be completely pumped out. Another 1000 ml of dichloromethane dried by molecular sieves was pumped into the heat exchange reactor by a peristaltic pump, and the pipeline was cleaned and transferred to the reactor containing ethanol). After all the liquids were transferred through the coils, the stirring reaction was continued for 2 hours.

[0058] Step 4 (post-processing):

[0059] The reaction solution after esterification was concentrated in the kettle to remove CH2Cl2 liquid, left to stand overnight, filtered, the filter cake was pulped with ethanol, filtered again, and vacuum dried to obtain 855g of white solid target of 2,5-dibromohexanedioic acid diethyl ester. The filtrates were combined twice, concentrated to half the volume and placed in a minus 20°C freezer for 2D, frozen for crystallization, filtered, and the filter cake was pulped with ethanol, filtered again, and vacuum dried to obtain 589g of white solid target, with a total yield of 55%. After the filtrates were combined twice and concentrated, it was found that in addition to a small amount of monobromo substitution, there were still a large amount of target (racemic body), and the mother liquor was retained and concentrated for distillation and purification.

[0060] Example 3

[0061] According to the procedure of Example 2, dimethyl 2,5-dibromoadipate was prepared in similar yield by using methanol instead of ethanol in the final esterification process.

[0062] As can be seen from the above embodiments, in Example 1 of the present invention, by designing a unique coil-shaped reaction device, the bromination reaction is carried out under continuous flow conditions, thereby improving the reaction efficiency and safety. At the same time, by controlling the rotation speed of the peristaltic pump and the temperature of the oil bath, the flow rate and reaction temperature of the reaction solution are accurately controlled, thereby optimizing the effect of the bromination reaction. In Example 2, the bromination reaction device is further improved, and a heat exchange reactor filled with a catalyst is introduced. This design not only improves the utilization rate and reaction rate of the catalyst, but also avoids the problem of catalyst blockage in the pipeline, making large-scale reactions possible. And in Example 2, by introducing homemade spherical catalyst particles, the rate of the bromination reaction is significantly accelerated, and the yield of the product is increased. In addition, the catalyst still maintains good activity after multiple reactions, reducing production costs. In the esterification stage, both Example 1 and Example 2 use anhydrous ethanol as an esterification agent, and by controlling the reaction temperature and time, the target product 2,5-dibromohexanoic acid diethyl ester is successfully prepared. In addition, Example 3 also demonstrates the feasibility of using methanol instead of ethanol for esterification, further broadening the scope of application of the method.

[0063] The above are only a few preferred embodiments of the present invention, which are described in a more specific and detailed manner, but they cannot be understood as limiting the scope of the present invention. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A process for preparing 2,5-dibromoadipate diester, characterized in that The following steps are involved: a. Chlorination step: reacting adipic acid with thionyl chloride in a reactor to obtain adipoyl chloride; b bromination step: the adipoyl chloride obtained in step a is mixed with liquid bromine, and the bromination reaction is carried out by a tubular reaction apparatus, wherein the tubular reaction apparatus adopts a tetrafluoroethylene coil heating form to reduce the loss of bromine and improve the reaction efficiency; c. Esterification step: The bromination product of step b is subjected to an esterification reaction with anhydrous ethanol in a reaction vessel to obtain diethyl 2,5-dibromoadipate; d. Post-treatment step: filtering, beating, drying, etc. the reaction solution obtained in step c to obtain the final product 2,5-dibromoadipate diester.

2. The preparation process according to claim 1, characterized in that: In step b, the tubular reaction device is filled with a granular catalyst, which is made by mixing red phosphorus, silica gel and molecular sieve, and is placed in the tubular reaction device in the form of a filler to improve the efficiency of the bromination reaction.

3. The preparation process according to claim 2, characterized in that: The preparation method of the catalyst comprises: grinding red phosphorus into fine powder and then mixing it evenly with silica gel, adding CMC-Na solution of appropriate concentration to stir into a viscous paste, and then mixing it evenly with molecular sieve to prepare spherical catalyst particles, and then drying and activating.

4. The preparation process according to claim 1 or 2, characterized in that: In step b, the tubular reaction device is a heat exchange reaction device, the main outer barrel and the internal straight tubes are made of glass, and the multiple straight tubes are filled with catalyst particles to form a complete passage. The reaction liquid is heated during the flow and a bromination reaction occurs.

5. A device for preparing 2,5-dibromoadipate diester, characterized in that: The invention comprises a reaction kettle, a tubular reaction device and an esterification reaction kettle, wherein the tubular reaction device adopts a PTFE coil heating form, and is filled with a granular catalyst, wherein the catalyst is made by mixing red phosphorus, silica gel and molecular sieve, and is placed in the tubular reaction device in the form of a filler, the reaction kettle is used for carrying out an acyl chloride reaction, the tubular reaction device is used for carrying out a bromination reaction, and the esterification reaction kettle is used for carrying out an esterification reaction.

6. The device according to claim 5, characterized in that The tubular reaction device is a heat exchange reaction device, the main outer barrel and the internal straight tubes of which are both made of glass, and the multiple straight tubes are filled with catalyst particles to form a complete passage.

7. The device according to claim 5 or 6, characterized in that It also includes a peristaltic pump and a high-temperature circulating oil bath device. The peristaltic pump is used to suck out the mixed liquid in the reaction kettle and pump it into the tubular reaction device, and the high-temperature circulating oil bath device is used to provide heating for the tubular reaction device.

8. A 2,5-dibromoadipate diester, characterized in that The method is prepared by any one of claims 1 to 4.

9. A 2,5-dibromoadipate diester, characterized in that Prepared by the device described in any one of claims 1-4 and any one of claims 5-7.

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