CN114702377A

CN114702377A - Continuous flow synthesis of isobutyric acid

Info

Publication number: CN114702377A
Application number: CN202210387633.7A
Authority: CN
Inventors: 刘朝阳; 陆绎; 林小如; 黄圣哲; 施金烛; 马磊
Original assignee: East China University of Science and Technology
Current assignee: East China University of Science and Technology
Priority date: 2022-04-14
Filing date: 2022-04-14
Publication date: 2022-07-05

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 cheap water purifying agent sodium chlorite as an oxidant, using nonmetal compound TEMPO or 4-OH-TEMPO as a catalyst, and using isobutyric acid and sodium hypochlorite as initiators to directly oxidize isobutanol into isobutyric acid; a micro-reaction system is adopted, and comprises a constant flow pump, a micro mixer, a micro channel reactor, a constant temperature water bath and a receiver which are sequentially communicated. Compared with the prior art, the technical scheme of the invention has the advantages of short reaction time, high yield of the product isobutyric acid of more than 98%, continuous process, high automation degree, high space-time efficiency, high safety, simple operation, no organic solvent, simple post-treatment, low cost and easy industrial production.

Description

Continuous flow synthesis of isobutyric acid

Technical Field

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

Background

Isobutyric acid is an important organic acid, is mainly used for synthesizing isobutyrate products, such as methyl isobutyrate, propyl isobutyrate, isoamyl isobutyrate, benzyl isobutyrate and the like, can be used as edible spice, solvent and disinfectant, and is also used for pharmacy, organic synthesis and leather deliming.

Few reports of the preparation method of the isobutyric acid exist: (1) isobutyric acid can be prepared from isobutanol in basic medium in KMnO₄The product is prepared by oxidizing an oxidant and rectifying (compiled by Korea, handbook of organic preparation chemistry, Beijing chemical industry publishers, 1980: 196), and the yield is only 73-76%. (2) Zhao Chong et al reported the production of isobutyric acid by oxidation of isobutanol using the oxidation medium Cr (VI) in the presence of a Phase Transfer Catalyst (PTC) (Zhao Chong applied chemistry 1997, 14 (6): 87-89). (3) Isobutyric acid can also be synthesized by isobutyraldehyde liquid-phase oxidation and methacrylic acid gas-phase catalytic hydrogenation (Xuke, eds. "handbook of fine organic chemical materials and intermediates, chemical industry Press, 1998: 1-233). (4) Wangchenxiu et Al invented a method for synthesizing isobutyric acid from a gasified mixture of isobutyraldehyde and water under the action of a catalyst, the catalyst is composed of Cu, Zn, Al and an oxide of one or more elements selected from rare earths La, Ce and Y, and the reaction temperature is 200 ℃ and 350 ℃ (CN 1435405A).

The existing preparation methods use heavy metal catalysts or oxidants, so that the defects of more three wastes, high energy consumption and high cost exist, and the methods are still carried out in the traditional batch type reaction kettle, so that the defects of high construction cost, long reaction time, complex operation, large potential safety hazard, low process efficiency and the like exist. Therefore, based on the problems of the existing preparation methods, the development of a continuous preparation method with short reaction time, low energy consumption, high process efficiency and intrinsic safety is a problem to be solved by those skilled in the art.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides a continuous flow synthesis method of isobutyric acid, which establishes a set of low-toxicity and low-price catalytic oxidation system and adopts a continuous flow reaction mode, so that the reaction time can be greatly shortened, the automation degree and efficiency of the process are obviously improved, the energy consumption is greatly reduced, the safety is greatly improved, and the method is easy for industrial application.

The invention provides a continuous flow synthesis method of isobutyric acid, which comprises the following steps:

(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 microchannel reactor, and separating and purifying to obtain the target product isobutyric acid.

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

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

Preferably, the initiator in the reaction solution a in the step (1) is isobutyric acid in an amount of 10 to 60 mol%.

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

Preferably, the oxidant in the reaction solution B in the step (1) is 100 to 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 to 15 minutes.

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

Preferably, the temperature of the thermostatic water bath in the step (2) is set to be 40-70 ℃.

Preferably, the step (3) specifically includes: 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.

Compared with the prior synthesis technology adopting the traditional batch reaction kettle, the invention has the beneficial effects that:

1. the reaction system has no organic solvent, the oxidant is cheap common water purifying agent sodium chlorite, only a small amount of non-metal 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 the initiator, the reaction is efficient and green, the materials are easy to obtain and cheap, and the post-treatment separation is simple.

2. If the reaction system is operated intermittently, severe reactions such as temperature runaway and the like can occur, close temperature control is needed, and the reaction is slowly dripped, so that the industrial application potential of the reaction system is limited. The system is developed based on the continuous flow process of the microchannel reactor, the total volume of a reaction fluid channel is small, so that the online liquid holdup is small, and the reaction process is intrinsically safe; has excellent mass and heat transfer and material mixing performance, and greatly shortens the reaction time.

3. The multiphase mixing, mass transfer and reaction processes of the continuous flow reaction process are finished in the reaction fluid channels of the micro mixer and the micro channel reactor, a stirring device is not needed, and the energy consumption of the process is greatly reduced.

4. The continuous flow realizes the continuous synthesis from raw materials to products, the technological process is continuously carried out, the automation degree is high, no external intervention is needed in the middle, the space-time efficiency is high, the number of operators and the labor intensity are greatly reduced, the production cost is obviously reduced, and the sustainability of the reaction is realized under many emergency situations.

Drawings

FIG. 1 is a schematic view of a flow of a micro reaction system in a continuous flow synthesis method of isobutyric acid according to the present invention.

FIG. 2 is a gas phase detection diagram of a reaction effluent in the continuous flow synthesis process of isobutyric acid according to the present invention.

Reference numerals

1 first reagent bottle

2 second reagent bottle

3 first flat flow pump

4 second advection pump

5 micro mixer

6 micro-channel reactor

7 constant temperature water bath

8 receiver

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1:

reagents and solvents: are all commercial products; the used solvents are domestic analytical pure reagents, are purchased from national pharmaceutical group chemical reagent limited company, and are not treated before use.

Gas chromatography: the GC 2010.

The implementation steps are as follows:

(1) measuring 46.33g (625mmol) of substrate isobutanol, 16.55g (187.5mmol, 0.3eq) of initiator isobutyric acid and 1.12g (6.25mmol, 0.01eq) of catalyst 4-OH-TEMPO by using an electronic balance, uniformly mixing, marking as reaction liquid A, measuring the volume by using a measuring cylinder to be about 70ml, and placing the reaction liquid A into a first reagent bottle 1;

(2) 84.40g (750mmol, 1.2eq) of sodium chlorite with 80 wt% of oxidant is weighed, a proper amount of water is added to be stirred and dissolved, 92.50g (93.75mmol, 0.15eq) of sodium hypochlorite with 7.5 wt% of initiator is weighed, the two solutions are transferred into a measuring cylinder, water is added to the total volume of about 700ml, the total volume is marked as reaction solution B, and the reaction solution B is placed in a second reagent bottle 2;

(3) a device is built according to the process flow of the attached drawing, and a reagent bottle, a constant-flow pump (a first reagent bottle 1 is connected with a first constant-flow pump 3, a second reagent bottle 2 is connected with a second constant-flow pump 4), a Y-shaped micro mixer, a constant-temperature water bath kettle and a conical flask are sequentially connected by using a micro-channel tube. Wherein, a microchannel tube between the micro mixer and the conical flask is a reaction area, the length of the tube is 10m, and the diameter of the tube is 1 mm;

(4) opening the constant temperature water bath kettle, and controlling the temperature of the constant temperature water bath kettle to be about 50 ℃;

(5) calculating the transmission rate ratio of the constant-flow pump according to the volume ratio of the two reaction liquids, setting the flow rate of the first constant-flow pump 3 to be 0.30ml/min, and setting the flow rate of the second constant-flow pump 4 to be 3.00 ml/min;

(6) simultaneously starting two advection pumps, conveying the reaction liquid A and the reaction liquid B to a Y-shaped micro mixer through the advection pumps for mixing, entering a micro-channel tube arranged in a 50 ℃ constant-temperature water bath kettle for continuous catalytic oxidation reaction, collecting the effluent product mixed liquid in a conical flask, and keeping the reaction liquid in the micro-channel for about 15 min;

(7) gas phase detection of the effluent showed complete reaction of isobutanol as substrate (conversion > 99%) and pure product (selectivity > 98%), as shown in figure 2;

(8) after the reaction is finished, transferring the reaction liquid in the conical flask to a separating funnel, standing for layering, collecting an upper organic phase, extracting a lower aqueous phase once by using dichloromethane (300ml), combining all the organic phases, neutralizing by using sodium sulfite, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain the target product isobutyric acid, wherein the purity is more than 98%, and the yield is 98% (minus initiator isobutyric acid).

Experimental example 2:

this example is identical to the experimental procedure of example 1, the only difference being that the catalyst used is 30 mol% TEMPO. The target product, isobutyric acid, was obtained in 97% purity and 99% yield (minus initiator, isobutyric acid).

Experimental example 3:

this example is identical to the experimental procedure of example 1, with the only difference that 0.5 mol% of 4-OH-TEMPO is used as catalyst. The target product, isobutyric acid, was obtained in 94% purity and 93% yield (minus initiator isobutyric acid).

Experimental example 4:

this example is identical to the experimental procedure of example 1, the only difference being that the initiators used are 10 mol% of isobutyric acid and 5 mol% of sodium hypochlorite. The target product isobutyric acid was obtained in a purity of greater than 98% and in a yield of 98% (minus initiator isobutyric acid).

Experimental example 5:

this example is identical to the experimental procedure of example 1, the only difference being that the initiators used are 60 mol% of isobutyric acid and 20 mol% of sodium hypochlorite. The target product, isobutyric acid, was obtained in a purity of greater than 98% and in a yield of 98% (minus initiator, isobutyric acid).

Experimental example 6:

this was carried out in the same manner as in example 1, except that 200 mol% sodium chlorite was used as the oxidizing agent. The target product isobutyric acid was obtained in a purity of greater than 98% and in a yield of 98% (minus initiator isobutyric acid).

Experimental example 7:

this example is identical to the experimental procedure of example 1, the only difference being that 100 mol% sodium chlorite is used as the oxidant. The target product isobutyric acid was obtained in a purity of greater than 98% and in a yield of 96% (minus initiator isobutyric acid).

Experimental example 8:

this was carried out in the same manner as in example 1, except that a reaction temperature of 40 ℃ was used. The target product, isobutyric acid, was obtained in 94% purity and 96% yield (minus initiator isobutyric acid).

Experimental example 9:

this was carried out in the same manner as the experimental procedure of example 1, with the only difference that a reaction temperature of 70 ℃ was used. The target product isobutyric acid was obtained in a purity of greater than 98% and in a yield of 98% (minus initiator isobutyric acid).

Experimental example 10:

this example is the same as the experimental procedure of example 1, the only difference being that the flow rate of the reaction solution is increased so that the reaction solution retention time is about 5 min. The target product isobutyric acid was obtained in a purity of greater than 98% and in a yield of 98% (minus initiator isobutyric acid).

Experimental example 11:

this example is the same as the experimental procedure of example 1, the only difference being the use of a T-type micromixer. The target product isobutyric acid was obtained in a purity of greater than 98% and in a yield of 98% (minus initiator isobutyric acid).

Experimental example 12:

this was carried out in the same manner as the experimental procedure of example 1, with the only difference that a static micromixer was used. The target product isobutyric acid was obtained in a purity of greater than 99% and in a yield of 98% (minus initiator isobutyric acid).

Experimental example 13:

this example was the same as the experimental procedure of example 1, except that a plate-type microreactor (a rectangular glass material having a length of 20cm, a width of 10cm and a thickness of 1cm, a microchannel having a length of 4m, a reaction solution holding volume of 7mL) was used, and the retention time was about 5 min. The target product, isobutyric acid, was obtained in a purity of greater than 99% and in a yield of 98% (minus the initiator, isobutyric acid).

Comparative example 1:

the catalytic oxidation system was applied to a batch operation:

46.33g (625mmol) of isobutanol, 16.55g (187.5mmol, 0.3eq) of isobutyric acid and 1.12g (6.25mmol, 0.01eq) of 4-OH-TEMPO are weighed into a 1000mL three-necked round-bottomed flask, and the reaction apparatus is heated in a water bath at 50 ℃. 84.40g (750mmol, 1.2eq) of 80 wt% sodium chlorite is weighed, a proper amount of water is added to be stirred and dissolved, 92.50g (93.75mmol, 0.15eq) of 7.5 wt% sodium hypochlorite is weighed as an initiator, the prepared mixed solution is placed in a constant-pressure dropping funnel, and then the reaction is dripped at the temperature of 50 ℃. During the reaction, the phenomenon of rapid temperature rise is observed, and an oxidant aqueous solution is required to be slowly dripped; when the oxidant drops into the reaction liquid, the reaction liquid turns reddish brown immediately and then fades to light yellow quickly. After about 6h of addition, stirring was continued for 10min, the reaction solution was finally pale yellow, and gas chromatographic monitoring indicated that the substrate isobutanol reacted completely (conversion > 99%) and the product was present as a significant impurity (selectivity 95%). Transferring the reaction solution to a separating funnel, standing for layering, collecting an upper organic phase, extracting a lower aqueous phase once with dichloromethane (300ml), combining all organic phases, neutralizing with a proper amount of sodium sulfite, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain the target product isobutyric acid with the purity of 95% and the yield of 98% (subtracting the initiator isobutyric acid).

The feed ratio of comparative example 1 and example 1 is the same, but the batch operation has severe reaction phenomena such as temperature runaway and the like, needs close temperature control, needs slow dropwise reaction, and has poorer reaction result than a continuous flow process. The continuous flow process based on the microchannel reactor has the advantages that the total volume of a reaction fluid channel is small, so that the online liquid holdup is small, and the reaction process is intrinsically safe; the catalyst has excellent mass and heat transfer and material mixing performance, so that the reaction time is greatly shortened; the time, economy and labor cost required by separation and repeated use in the batch kettle type reaction process are saved (the batch kettle type reaction process needs to be fed again after the reaction is finished and the corresponding complex reaction operation procedure is carried out).

In this specification, the invention has been described with reference to specific embodiments thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention. The description is thus to be regarded as illustrative instead of limiting.

Claims

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

(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.