CN114702377A - Continuous flow synthesis method of isobutyric acid - Google Patents

Abstract

The invention relates to a continuous flow synthesis method of isobutyric acid, which comprises the following steps: under the condition of no organic solvent, using a cheap water purifying agent sodium chlorite as an oxidant, a non-metallic compound TEMPO or 4-OH-TEMPO as a catalyst, Isobutyric acid and sodium hypochlorite are used as initiators to directly oxidize isobutanol to isobutyric acid; a micro-reaction system is adopted, and the micro-reaction system includes an advection pump, a micro-mixer, a micro-channel reactor, a constant temperature water bath and a receiver connected in sequence. Compared with the prior art, the technical scheme of the present invention has short reaction time, yield of product isobutyric acid is greater than 98%, continuous process, high degree of automation, high space-time efficiency, high safety, easy operation, no organic solvent, post-processing The processing is simple, the cost is low, and the industrial production is easy.

Description

Continuous flow synthesis method of isobutyric acid

technical field

The invention relates to the technical field of preparation of fine chemical products, in particular to the technical field of preparation of isobutyric acid, in particular to a continuous flow synthesis method of isobutyric acid.

Background technique

Isobutyric acid is an important organic acid, mainly used in the synthesis of isobutyrate products, such as methyl isobutyrate, propyl ester, isoamyl ester, benzyl ester, etc. It can be used as food flavoring, solvent, disinfectant, Also used in pharmaceuticals, organic synthesis, leather deliming.

There are few reports on the preparation methods of isobutyric acid: (1) Isobutyric acid can be obtained by rectifying isobutanol after oxidation with KMnO ₄ as an oxidant in an alkaline medium (Han Guangdian compiled "Handbook of Organic Preparative Chemistry", Beijing Chemistry Industrial Press, 1980: 196), the yield is only 73% to 76%. (2) Zhao Chongtao et al reported the preparation of isobutyric acid by oxidizing isobutanol in the presence of phase transfer catalyst (PTC) using oxidizing medium Cr(Ⅵ) (Zhao Chongtao "Applied Chemistry" 1997, 14(6): 87-89). (3) isobutyric acid can also be synthesized by isobutyraldehyde liquid-phase oxidation method and methacrylic acid gas-phase catalytic hydrogenation method (Xu Kexun edited "Fine Organic Chemical Raw Materials and Intermediates Handbook", Chemical Industry Press, 1998: 1-233 ). (4) Wang Hengxiu et al. invented a method for synthesizing isobutyric acid from a gasification mixture of isobutyraldehyde and water under the action of a catalyst. The catalyst is composed of Cu, Zn, Al and one or more elements selected from rare earths La, Ce and Y. The oxide composition of , the reaction temperature is 200-350 ℃ (CN1435405A).

These existing preparation methods use heavy metal catalysts or oxidants, which not only have the disadvantages of many wastes, high energy consumption, and high cost, but also these methods are still carried out in traditional batch reactors, and have the disadvantages of high construction cost, long reaction time, It has disadvantages such as complicated operation, big safety hazard and low process efficiency. Therefore, based on the problems existing in the existing preparation methods, it is an urgent problem for those skilled in the art to develop a continuous preparation method with short reaction time, low energy consumption, high process efficiency and intrinsic safety.

SUMMARY OF THE INVENTION

In order to overcome the deficiencies of the prior art, the present invention provides a continuous flow synthesis method of isobutyric acid, which establishes a low-toxic and cheap catalytic oxidation system, and adopts a continuous flow reaction mode, which can make the reaction time extremely short. It is greatly shortened, the degree of automation and efficiency of the process is significantly improved, the energy consumption is greatly reduced, the safety is greatly improved, and it is easy to industrialize applications.

A kind of continuous flow synthesis method of isobutyric acid provided by the invention, the concrete steps are:

(1) prepare the reaction solution A containing isobutanol, initiator and catalyzer and the reaction solution B containing initiator and oxidant;

(2) use 2 advection pumps to transport the reaction solutions A and B into the micro-mixer at a certain rate respectively, and then carry out the continuous catalytic oxidation reaction in the micro-channel reactor in a constant temperature water bath;

(3) collecting the reaction mixture flowing out from the microchannel reactor, and separating and purifying to obtain the target product isobutyric acid.

Preferably, the reaction formula of the oxidation reaction described in the step (2) is:

Preferably, the catalyst in the reaction solution A in the step (1) is 0.5-30 mol% TEMPO or 0.5-30 mol% 4-OH-TEMPO.

Preferably, the initiator in the reaction solution A described in the step (1) is 10-60 mol% of isobutyric acid.

Preferably, the initiator in the reaction solution B in the step (1) is 5-20 mol% of sodium hypochlorite.

Preferably, the oxidant in the reaction solution B in the step (1) is 100-200 mol% of sodium chlorite.

Preferably, the residence time of the reaction solution A and the reaction solution B in the microchannel reactor in the step (2) is 5-15 minutes.

Preferably, the micro-mixer described in the step (2) is one of a static mixer, a T-type micro-mixer, and a Y-type micro-mixer.

Preferably, the microchannel reactor described in the step (2) is a tubular microchannel reactor or a plate microchannel reactor, and the inner diameter is 100 micrometers to 50 mm.

Preferably, the temperature of the constant temperature water bath in the step (2) is set at 40-70°C.

Preferably, the step (3) specifically includes: collecting the reaction mixture flowing out of the micro-reaction system, and obtaining the target product isobutyric acid after liquid separation, extraction, drying and concentration under reduced pressure.

Compared with the existing synthesis technology that adopts traditional batch reactor, the beneficial effects of the present invention are:

1. There is no organic solvent in the reaction system, the oxidant is the cheap and common water purifier sodium chlorite, only a very small amount of non-metallic compound TEMPO or 4-OH-TEMPO is used as the catalyst, the target product isobutyric acid and the bleaching agent sodium hypochlorite are used As an initiator, the reaction is efficient and green, the materials are easy to obtain and cheap, and the post-processing and separation are simple.

2. If the reaction system is operated intermittently, violent reactions such as flying temperature will occur, and it is necessary to closely control the temperature and slowly drop the reaction, which limits its industrial application potential. The development of the system is based on the continuous flow process of the microchannel reactor. The total volume of the reaction fluid channel is small, so that the online liquid holdup is small, and the reaction process is intrinsically safe; it has excellent mass transfer, heat transfer and material mixing performance, which greatly shortens the reaction time. .

3. The multiphase mixing, mass transfer and reaction process of the continuous flow reaction process are completed in the reaction fluid channel of the micro-mixer and the micro-channel reactor, without the need for a stirring device, which greatly reduces the energy consumption of the process.

4. Continuous flow realizes continuous synthesis from raw materials to products. The process is continuous and uninterrupted, with a high degree of automation, no external intervention in the middle, high time and space efficiency, greatly reducing the number of operators and labor intensity, significantly reducing production costs, and in many Sustainability of responses in emergencies.

Description of drawings

1 is a schematic flow diagram of a micro-reaction system in the continuous flow synthesis method of isobutyric acid of the present invention.

Fig. 2 is the gas phase detection diagram of the reaction effluent in the continuous flow synthesis method of isobutyric acid of the present invention.

reference number

1 First reagent bottle

2 Second reagent bottle

3 The first advection pump

4 Second advection pump

5 Micro mixers

6 Microchannel Reactors

7 Constant temperature water bath

8 Receivers

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

Example 1:

Reagents and solvents: both are commercially available; the solvents used are domestic analytical reagents, purchased from Sinopharm Chemical Reagent Co., Ltd., without any treatment before use.

Gas Chromatography: GC2010.

Implementation steps:

(1) Use an electronic balance to measure 46.33g (625mmol) of isobutanol as substrate, 16.55g (187.5mmol, 0.3eq) of initiator isobutyric acid, and 1.12g (6.25mmol, 0.01eq) of catalyst 4-OH-TEMPO, Mix evenly, denoted as reaction solution A, measure its volume with a measuring cylinder to be about 70ml, and place it in the first reagent bottle 1;

(2) Weigh 84.40g (750mmol, 1.2eq) of sodium chlorite of 80wt% oxidant, add an appropriate amount of water and stir to dissolve, and weigh 92.50g (93.75mmol, 0.15eq) of initiator 7.5wt% sodium hypochlorite, the above two The solution is transferred to a graduated cylinder, and water is added to a total volume of about 700ml, which is denoted as reaction solution B, which is placed in the second reagent bottle 2;

(3) Build the device according to the process flow of the attached drawing, and connect the reagent bottle, the advection pump (the first reagent bottle 1 is connected to the first advection pump 3, the second reagent bottle 2 is connected to the second advection pump 4), Y Micro-mixer, constant temperature water bath, conical flask. Among them, the inside of the microchannel tube between the micromixer and the conical flask is the reaction area, the tube length is 10m, and the tube diameter is 1mm;

(4) Open the constant temperature water bath and control its temperature to be kept at about 50°C;

(5) calculate the advective pump transmission rate ratio according to the volume ratio of two reaction solutions, set the flow rate of the first advection pump 3 to be 0.30ml/min, and set the flow rate of the second advection pump 4 to be 3.00ml/min;

(6) Start two advection pumps at the same time, and the reaction solution A and the reaction solution B are transported to the Y-type micro-mixer by the advection pump to mix, enter the microchannel tube placed in a 50°C constant temperature water bath for continuous catalytic oxidation reaction, and flow out The product mixture is collected in a conical flask, and the reaction solution is retained in the microchannel for about 15 minutes;

(7) The effluent is detected by gas phase, showing that the reaction of the substrate isobutanol is complete (conversion rate>99%), and the product is pure (selectivity>98%), as shown in Figure 2;

(8) After the completion of the reaction, transfer the reaction solution in the conical flask to a separatory funnel, let stand for stratification, collect the upper organic phase, extract the lower aqueous phase once with dichloromethane (300 ml), combine all the organic phases, pass through sodium sulfite Neutralize and dry with anhydrous sodium sulfate, suction filtration, and concentrate the filtrate under reduced pressure to obtain the target product isobutyric acid with a purity of more than 98% and a yield of 98% (minus the initiator isobutyric acid).

Experimental example 2:

This implementation is the same as the experimental procedure of Example 1, the only difference is that the catalyst used is 30 mol% TEMPO. The target product isobutyric acid was obtained with a purity of 97% and a yield of 99% (minus the initiator isobutyric acid).

Experimental example 3:

This implementation is the same as the experimental procedure of Example 1, the only difference is that the catalyst used is 0.5 mol% 4-OH-TEMPO. The target product isobutyric acid was obtained with a purity of 94% and a yield of 93% (minus the initiator isobutyric acid).

Experimental example 4:

This implementation is the same as the experimental procedure of Example 1, the only difference is that the initiators used are 10 mol% isobutyric acid and 5 mol% sodium hypochlorite. The obtained target product isobutyric acid has a purity of more than 98% and a yield of 98% (minus the initiator isobutyric acid).

Experimental example 5:

This implementation is the same as the experimental procedure in Example 1, the only difference is that the initiators used are 60 mol% isobutyric acid and 20 mol% sodium hypochlorite. The target product isobutyric acid was obtained with a purity greater than 98% and a yield of 98% (minus the initiator isobutyric acid).

Experimental example 6:

This implementation is the same as the experimental procedure of Example 1, the only difference is that the oxidant used is 200 mol% sodium chlorite. The target product isobutyric acid was obtained with a purity of more than 98% and a yield of 98% (minus the initiator isobutyric acid).

Experimental example 7:

This implementation is the same as the experimental procedure of Example 1, the only difference is that the oxidant used is 100 mol% sodium chlorite. The target product isobutyric acid was obtained with a purity of more than 98% and a yield of 96% (minus the initiator isobutyric acid).

Experimental example 8:

This implementation is the same as the experimental procedure of Example 1, the only difference is that the reaction temperature used is 40°C. The target product isobutyric acid was obtained with a purity of 94% and a yield of 96% (minus the initiator isobutyric acid).

Experimental example 9:

This implementation is the same as the experimental procedure of Example 1, the only difference is that the reaction temperature used is 70°C. The target product isobutyric acid was obtained with a purity of more than 98% and a yield of 98% (minus the initiator isobutyric acid).

Experimental example 10:

This implementation is the same as the experimental procedure of Example 1, the only difference is that the flow rate of the reaction solution is accelerated so that the retention time of the reaction solution is about 5 min. The target product isobutyric acid was obtained with a purity of more than 98% and a yield of 98% (minus the initiator isobutyric acid).

Experimental example 11:

This implementation is the same as the experimental procedure of Example 1, the only difference is that a T-type micro-mixer is used. The target product isobutyric acid was obtained with a purity of more than 98% and a yield of 98% (minus the initiator isobutyric acid).

Experimental example 12:

This implementation is the same as the experimental procedure of Example 1, the only difference is that a static micro-mixer is used. The target product isobutyric acid was obtained with a purity greater than 99% and a yield of 98% (minus the initiator isobutyric acid).

Experimental example 13:

This implementation is the same as the experimental procedure in Example 1. The only difference is that a plate-type microreactor (20cm long, 10cm wide and 1cm thick cuboid glass material, the length of the microchannel is 4m, and the volume of the reaction solution is 7mL) is used, and the retention time is about 5min. . The target product isobutyric acid was obtained with a purity greater than 99% and a yield of 98% (minus the initiator isobutyric acid).

Comparative Example 1:

Applying this catalytic oxidation system to batch operation:

Weigh 46.33g (625mmol) of isobutanol, 16.55g (187.5mmol, 0.3eq) of isobutyric acid, 1.12g (6.25mmol, 0.01eq) of 4-OH-TEMPO, put them in a 1000mL three-neck round bottom flask, and then react The device was heated in a 50°C water bath. Weigh 84.40g (750mmol, 1.2eq) of 80wt% sodium chlorite, add an appropriate amount of water and stir to dissolve, and weigh 7.5wt% sodium hypochlorite 92.50g (93.75mmol, 0.15eq) as an initiator, and place the prepared mixed solution in a constant Press the dropping funnel, and then add the reaction dropwise at 50 degrees Celsius. The phenomenon of rapid temperature rise was observed in the reaction, and the oxidant aqueous solution should be slowly added dropwise; when the oxidant droplets entered the reaction solution, the reaction solution immediately turned reddish-brown, and then quickly faded to light yellow. The dropwise addition was completed for about 6h, and the stirring reaction was continued for 10min. The reaction solution was finally pale yellow. The gas chromatography monitoring showed that the reaction of the substrate isobutanol was complete (conversion rate>99%), and the product had obvious impurities (selectivity 95%). Transfer the reaction solution to a separatory funnel, let stand for layers, collect the upper organic phase, extract the lower aqueous phase once with dichloromethane (300 ml), combine all organic phases, neutralize with an appropriate amount of sodium sulfite, dry over anhydrous sodium sulfate, and filter with suction , the filtrate was concentrated under reduced pressure to obtain the target product isobutyric acid with a purity of 95% and a yield of 98% (minus the initiator isobutyric acid).

The charging ratio of Comparative Example 1 and Example 1 is the same, but the intermittent operation will have violent reactions such as flying temperature, which requires close temperature control, and requires very slow dropwise reaction, and the reaction result is also worse than the continuous flow process. The continuous flow process based on the microchannel reactor, the total volume of the reaction fluid channel is small, so that the online liquid holdup is small, and the reaction process is intrinsically safe; it has excellent mass transfer, heat transfer and material mixing performance, which greatly shortens the reaction time; saves intermittent The time, economy and labor cost required for separation and repeated use in the tank reaction process (the batch tank reaction process requires re-feeding and corresponding complex reaction operation procedures after the reaction is completed).

In this specification, the invention has been described with reference to specific embodiments thereof. However, it will be evident that various modifications and changes can still be made without departing from the spirit and scope of the invention. Accordingly, the description is to be regarded as illustrative rather than restrictive.

Claims (11)

1. A method for the continuous flow synthesis of isobutyric acid, said method comprising the steps of:

(1) preparing reaction liquid A containing isobutanol, an initiator and a catalyst and reaction liquid B containing the initiator and an oxidant;

(2) respectively and simultaneously conveying reaction liquids A and B into a micro mixer at a certain ratio by using 2 constant-flow pumps, and then carrying out continuous catalytic oxidation reaction in a micro-channel reactor in a constant-temperature water bath kettle;

(3) and collecting the reaction mixed liquor flowing out of the reactor in the microchannel, and separating and purifying to obtain the target product isobutyric acid.

2. The continuous flow synthesis process of isobutyric acid according to claim 1, wherein the reaction formula of the oxidation reaction in step (2) is:

3. the continuous-flow synthesis method of isobutyric acid according to claim 1, wherein the catalyst in the reaction solution A in the step (1) is TEMPO of 0.5 to 30 mol% or 4-OH-TEMPO of 0.5 to 30 mol%.

4. The continuous-flow synthesis method of isobutyric acid according to claim 1, wherein the initiator in the reaction solution A in the step (1) is 10 to 60 mol% of isobutyric acid.

5. The continuous-flow synthesis method of isobutyric acid as claimed in claim 1, wherein the initiator in the reaction solution B in step (1) is sodium hypochlorite of 5-20 mol%.

6. The continuous flow synthesis method of isobutyric acid according to claim 1, wherein the oxidant in the reaction solution B in the step (1) is 100 to 200 mol% sodium chlorite.

7. The continuous-flow synthesis method of isobutyric acid according to claim 1, wherein the residence time of the reaction solution A and the reaction solution B in the microchannel reactor in the step (2) is 5 to 15 minutes.

8. The continuous flow synthesis method of isobutyric acid according to claim 1, wherein the micromixer in step (2) is one of a static mixer, a T-type micromixer, and a Y-type micromixer.

9. The continuous flow synthesis of isobutyric acid as claimed in claim 1, wherein the microchannel reactor in step (2) is a tubular microchannel reactor or a plate microchannel reactor having an inner diameter of 100 μm to 50 mm.

10. The method of claim 1, wherein the temperature of the thermostatic waterbath in step (2) is set to 40-70 ℃.

11. The continuous flow synthesis process of isobutyric acid according to claim 1, wherein the step (3) comprises: and collecting the reaction mixed liquor flowing out of the micro-reaction system, and carrying out liquid separation, extraction, drying and reduced pressure concentration to obtain the target product isobutyric acid.

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