Fully continuous flow preparation method of valproic acid

Abstract

The invention belongs to the technical field of organic chemical engineering, and particularly relates to a full-continuous flow preparation method of valproic acid. The method comprises the following steps: conveying alkali liquor and an organic solution containing acetoacetate, allyl halide and a catalyst into a mixer, then feeding the alkali liquor and the organic solution into a first reactor for continuous allylation reaction, mixing the outflowing reaction liquid with water, feeding the mixture into a gravity separation column for continuous liquid separation, and recovering a solvent from an organic phase through a continuous concentration device; a high-boiling-point product is conveyed to a mixer from the bottom of the continuous concentration device to be mixed with organic alkali and then enters a second reactor for continuous deacetylation; the reaction liquid and hydrogen are mixed and enter a packed bed reactor for continuous hydrogenation, and the mixture and an inorganic alkali aqueous solution pass through a mixer and then are conveyed into a fourth reactor for continuous hydrolysis reaction; and mixing the reaction liquid with a hydrochloric acid aqueous solution, continuously acidifying, and finally, continuously extracting and separating to obtain a target product. The method is short in reaction time, high in efficiency, high in space-time yield, low in energy consumption and easy to industrially amplify and apply.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic chemical engineering, and particularly relates to a full continuous flow preparation method of valproic acid. BACKGROUND

[0002] Valproic acid is an important fine chemical intermediate, which is applied to the medicine, pesticide and dye industry and has a very wide application prospect, for example, is used for preparing antiepileptic drug sodium valproate. Its structural formula is shown as formula (I):

[0003]

[0004] US4127604 discloses a method for synthesizing valproic acid by using cyanoacetate as a raw material. Although the raw material is easy to obtain, explosive metal sodium is used, and a large amount of nitrogen dioxide is generated during hydrolysis of the cyano group, which is not suitable for industrialization. US5856569 discloses a method for synthesizing valproic acid by using acetoacetate as a raw material. A large amount of bromopropane is used, and the yield is low, which is not suitable for industrial production. Wu Changzeng (Chemical Engineer, 2015, 29(8), 10-15) reports a method for preparing valproic acid by using diethyl malonate as a raw material. The method uses reagents with high prices, and the production cost is high. SUMMARY

[0005] The purpose of the present application is to provide a full continuous flow preparation method of valproic acid with high efficiency, low energy consumption and good safety, so as to overcome the problems of long reaction time, great safety hazard, high energy consumption and low efficiency of the traditional batch kettle synthesis method.

[0006] The method has low raw material cost, shortened reaction time, significantly improved automation degree and efficiency of the process, greatly reduced energy consumption, greatly improved safety, and is easy to be applied in industry.

[0007] The full continuous flow preparation method of valproic acid provided by the present application uses a reaction system composed of a plurality of mixers and a plurality of continuous flow reactors and auxiliary components connected in sequence, and the specific steps are as follows:

[0008] (1) The organic alkali solution and the organic solution containing acetoacetate, allyl halide and catalyst are simultaneously transported to the first mixer, mixed and then entered into the first reactor (under appropriate temperature, pressure and reaction time conditions), to perform continuous allylation reaction, and a first reaction liquid is obtained;

[0009] (2) The first reaction liquid flowed out in step (1) is quenched by water and then enters the first gravity separation column for continuous liquid separation. The organic phase is recovered by a continuous solvent recovery device, and a diallylated product (IV) is obtained.

[0010] (3) The double allyl product (IV) flowed out in step (2) is mixed with an organic base through a second mixer, and then is delivered into a second reactor to continuously deacetylate under certain temperature, pressure and reaction time conditions, so as to obtain a second reaction liquid containing the deacetylated product (V);

[0011] (4) The second reaction liquid flowed out in step (3) is mixed with hydrogen through a third mixer, and then is delivered into a third reactor (a fixed bed reactor) pre-filled with a catalyst to continuously hydrogenate under a preheated reaction temperature and pressure, so as to obtain a third reaction liquid containing the hydrogenated product (VI);

[0012] (5) The third reaction liquid flowed out in step (4) is mixed with an inorganic base aqueous solution through a fourth mixer, and then is delivered into a fourth reactor to continuously hydrolyze, so as to obtain a fourth reaction liquid containing the hydrolyzed product sodium valproate;

[0013] (6) The fourth reaction liquid flowed out in step (5) is mixed with a hydrochloric acid aqueous solution through a fifth mixer, and then is delivered into a fifth reactor to continuously acidize, and finally is continuously extracted and separated through a second gravity separation column to obtain the valproic acid product (I);

[0014] The chemical reaction formula is as follows:

[0015]

[0016] In the formula, R1 is a C1-C4 alkyl group; R2 is a C1-C4 alkyl group; X is Cl, Br or I; M is potassium or sodium; compound (II) is a substituted acetoacetate, compound (III) is an allyl halide, compound (IV) is a double allyl product, compound (V) is a deacetylated product, compound (VI) is a hydrogenated product, and compound (I) is the target product.

[0017] base1 is an alkali solution; and base2 is an inorganic base aqueous solution;

[0018] The catalyst used for allylation is a quaternary ammonium salt, polyethylene glycol, Tween or a crown ether;

[0019] Further, in step (1):

[0020] In step (1):

[0021] The acetoacetate is one of methyl acetoacetate, ethyl acetoacetate, propyl acetoacetate and tert-butyl acetoacetate; and more preferably, the acetoacetate is methyl acetoacetate or ethyl acetoacetate;

[0022] The organic solvent is any one of an alcohol, a chlorinated hydrocarbon, an alkane and an aromatic hydrocarbon; and more preferably, the organic solvent is methanol, ethanol, dichloromethane, toluene or cyclohexane.

[0023] The catalyst is one of quaternary ammonium salt, polyethylene glycol, crown ether, Tween; more preferably the catalyst is quaternary ammonium salt or crown ether.

[0024] The allyl halide is one of allyl bromide, allyl chloride, allyl iodide; more preferably the allyl halide is allyl bromide, allyl chloride.

[0025] The base (base 1) is one of triethylamine, pyridine, piperidine, sodium methoxide, sodium ethoxide, sodium propoxide, sodium tert-butoxide, potassium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide or potassium carbonate; more preferably, base 1 is pyridine, piperidine, sodium methoxide, sodium ethoxide.

[0026] Preferably, the flow ratio of base and acetoacetate into the first reactor is controlled so that the molar ratio of acetoacetate, base, allyl halide, catalyst is 1:(1.0-5.0):(2.0-5.0):(0.01-0.5); more preferably the molar ratio is 1:(1.0-3.0):(2.0-3.0):(0.01-0.1).

[0027] Preferably, the temperature in the first reactor is controlled to be 20-150°C; the pressure in the first reactor is controlled to be 0-20 bar; the residence time of the mixed reaction materials in the first reactor is 0.1-60 minutes; more preferably the temperature is controlled to be 50-100°C, the pressure is controlled to be 0-10 bar, and the residence time is 0.1-20 minutes.

[0028] In step (2), the solvent removal device is an online continuous solvent recovery device.

[0029] In step (3):

[0030] The organic base is one of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide or potassium tert-butoxide;

[0031] The temperature in the second reactor is controlled to be 20-200°C; the pressure in the second reactor is controlled to be 0-50 bar; the residence time of the mixed reaction materials in the second reactor is 0.1-20 minutes; more preferably the organic base is sodium methoxide, potassium methoxide, sodium ethoxide; the temperature is controlled to be in the range of 20-150°C; the pressure in the reactor is controlled to be in the range of 0-20 bar; the residence time of the mixed reaction materials in the reactor is 0.1-10 minutes.

[0032] In step (4):

[0033] The catalyst pre-filled in the third reactor (fixed bed reactor) is one of palladium-carbon, platinum-carbon, Raney nickel;

[0034] The temperature in the third reactor is controlled at 0-150℃; the pressure in the third reactor is controlled at 0-100 bar; the residence time of the mixed reaction materials in the third reactor is 0.1-20 minutes; further preferably, the pre-packed catalyst in the fixed bed is palladium-carbon or platinum-carbon; the temperature is controlled at 20-100℃; the pressure in the reactor is controlled at 0-60 bar; the residence time of the mixed reaction materials in the reactor is 0.1-5 minutes.

[0035] In step (5):

[0036] The inorganic base (base2) is one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution or potassium carbonate aqueous solution;

[0037] The temperature in the fourth reactor is controlled at 20-200℃; the pressure in the fourth reactor is controlled at 0-50 bar; the residence time of the mixed reaction materials in the fourth reactor is 0.1-20 minutes; further preferably, the inorganic base is sodium hydroxide aqueous solution or potassium hydroxide aqueous solution; the temperature is controlled at 20-150℃; the pressure in the reactor is controlled at 0-20 bar; the residence time of the mixed reaction materials in the reactor is 0.1-10 minutes.

[0038] Preferably, the reactors in the continuous flow (including the first-fifth reactors) are dynamic tubular reactors, tubular reactors or plate reactors, and more preferably the continuous flow reactors are dynamic tubular reactors or tubular reactors.

[0039] The mixers in the continuous flow (including the first-fifth mixers) are any one of static mixers, T-type mixers, Y-type mixers, cross-type mixers, coaxial flow mixers or flow focusing mixers, and more preferably the mixers are Y-type mixers, coaxial flow mixers or flow focusing mixers.

[0040] The method for continuously preparing valproic acid (I) using the continuous flow reaction system can be conveniently implemented in industrial large-scale production through a multi-channel parallel amplification strategy.

[0041] Advantages

[0042] The method for preparing compound (I) using the continuous flow reaction system comprising mixers and continuous flow reactors connected in sequence has the following advantages compared with the traditional batch reaction kettle synthesis method:

[0043] The continuous flow reaction system has excellent mass transfer, heat transfer and material molecular mixing performance, so that the reaction time is greatly shortened and the reaction efficiency is greatly improved, from several days of traditional batch kettle reaction to about tens of minutes, greatly improving the danger of kettle high-temperature reaction. BRIEF DESCRIPTION OF DRAWINGS

[0044] Figure 1 The flow chart of the full continuous flow preparation method of valproic acid of the present application. DETAILED DESCRIPTION

[0045] To make a further explanation of the technical content, structural features, achieved purposes and effects of the technical scheme, the following will be further explained in combination with specific embodiments and the accompanying drawings. The embodiments are implemented on the premise of the technical scheme of the present application, and give detailed implementation modes and specific operation processes, but the protection scope of the present application is not limited to the following embodiments.

[0046] The structure of the reaction system used in the embodiments is shown in the accompanying drawings. Figure 1

[0047] The working process is as follows:

[0048] The lye and the organic solution containing acetoacetic ester, allyl halide and catalyst are simultaneously transported to the mixer and then into the reactor 1 to perform continuous allylation reaction. The effluent reaction liquid 1 is mixed with water and then transported into the gravity separation column to perform continuous liquid separation. The organic phase is transported to the continuous concentration device to recover the solvent. The high-boiling product is transported from the bottom of the continuous concentration device to the mixer, mixed with the organic base and then transported into the reactor 2 to perform continuous deacetylation. The effluent reaction liquid 2 is mixed with hydrogen and then transported into the packed bed reactor 3 filled with catalyst in advance to perform continuous hydrogenation. The effluent reaction liquid from the fixed bed is mixed with the inorganic base aqueous solution by the mixer and then transported into the reactor 4 to perform continuous hydrolysis reaction. The effluent reaction liquid 4 is mixed with the hydrochloric acid aqueous solution by the mixer and then continuously acidified. Finally, the target product is obtained by continuous extraction separation.

[0049] To better explain the purposes, technical scheme and advantages of the present application, the following will further explain the present application in combination with specific embodiments.

[0050] Example 1: Continuous flow preparation of valproic acid

[0051] ​A solution of sodium methoxide in methanol and a solution of methyl acetoacetate, allyl bromide, tetrapropylammonium bromide in methanol were simultaneously fed into a dynamic tubular reactor 1 (reaction volume 200 ml, channel diameter 10 mm) by a piston pump, the flow ratio of the pump was adjusted to make the molar ratio of methyl acetoacetate and sodium methoxide, allyl bromide, tetrapropylammonium bromide at 1:2.2:2.1:0.05, the temperature of the reaction liquid was controlled at 85°C, the residence time was 15 minutes, the back pressure of the system was 10 bar, the effluent was mixed with water and then separated by a gravity separation column online before entering the continuous concentration device to recover the solvent, the bis-allyl product was transported to a mixer and mixed with an organic base before entering reactor 2 for continuous deacetylation reaction (reaction volume 200 ml, channel diameter 10 mm), the temperature of the reaction liquid was controlled at 120°C, the residence time was 8 minutes, the effluent was mixed with hydrogen before entering a packed bed reactor 3 pre-filled with palladium-carbon for continuous hydrogenation reaction (reaction volume 100 ml, channel diameter 30 mm), the effluent from the fixed bed was mixed with sodium hydroxide aqueous solution by a mixer before being transported to reactor 4 for continuous hydrolysis reaction (reaction volume 30 ml, channel diameter 10 mm); the effluent 4 was mixed with hydrochloric acid aqueous solution by a mixer before being continuously acidified, and the target product was finally separated by continuous extraction, and pure valproic acid was obtained by continuous extraction with a total yield of 87% and a purity of 99.6%.

[0052] Example 2: Continuous flow preparation of valproic acid

[0053] This example is the same as example 1, the only difference is that the raw material used in this example is ethyl acetoacetate, and the obtained biotin has a yield of 85% and a purity of 99.8%.

[0054] Example 3: Continuous flow preparation of valproic acid

[0055] This example is the same as example 2, the only difference is that the reactor used in this example is a plate reactor, and the total yield is 81% and the purity is 99.1%.

[0056] Example 4: Continuous flow preparation of valproic acid

[0057] This example is the same as example 1, the only difference is that the catalyst filled in the fixed bed in this example is platinum-carbon, and the obtained valproic acid has a yield of 70% and a purity of 99.4%.

[0058] Example 5: Continuous flow preparation of valproic acid

[0059] This example is the same as example 3, the only difference is that allyl bromide is replaced by allyl chloride in this example, and the obtained valproic acid has a yield of 80% and a purity of 99.9%.

[0060] It should be noted that, although the above-mentioned embodiments have been described herein, the patent protection scope of the present application is not limited thereby. Therefore, based on the innovative idea of the present application, the changes and modifications made to the embodiments described herein, or the equivalent structures or equivalent process transformations made using the content of the present application specification and drawings, directly or indirectly apply the above technical solutions to other related technical fields, are all included in the patent protection scope of the present application.

Claims

1. A fully continuous flow process for the preparation of valproic acid, characterized in that, The reaction system is composed of multiple mixers, multiple continuous flow reactors and auxiliary components connected together, and the specific steps are as follows: (1) the organic base solution and the organic solution containing acetoacetic ester, allyl halide and catalyst are simultaneously delivered to the first mixer, mixed and then fed into the first reactor to perform continuous allylation reaction, thereby obtaining the first reaction liquid; (2) the first reaction liquid flowed out in step (1) is quenched by water and then fed into the first gravity separation column to perform continuous liquid separation, and the organic phase is recycled by the continuous solvent recycling device to obtain the diallylated product (IV); (3) the diallylated product (IV) flowed out in step (2) and the organic base are mixed by the second mixer and then delivered to the second reactor to perform continuous deacetylation, thereby obtaining the second reaction liquid containing the deacetylated product (V); (4) the second reaction liquid flowed out in step (3) and hydrogen are mixed by the third mixer and then delivered to the third reactor pre-filled with catalyst to perform continuous hydrogenation reaction, thereby obtaining the third reaction liquid containing the hydrogenated product (VI); (5) the third reaction liquid flowed out in step (4) and the inorganic base aqueous solution are mixed by the fourth mixer and then delivered to the fourth reactor to perform continuous hydrolysis reaction, thereby obtaining the fourth reaction liquid containing the hydrolyzed product sodium valproate; (6) the fourth reaction liquid flowed out in step (5) and the hydrochloric acid aqueous solution are mixed by the fifth mixer and then delivered to the fifth reactor to perform continuous acidification reaction, and finally the valproic acid product (I) is obtained by continuous extraction separation through the second gravity separation column; The chemical reaction formula is as follows: wherein, R1 is C1-C4 alkyl; R2 is C1-C4 alkyl; X is Cl, Br or I; M is potassium or sodium; compound (II) is substituted acetoacetic ester, compound (III) is allyl halide, compound (IV) is diallylated product, compound (V) is deacetylated product, compound (VI) is hydrogenated product, and compound (I) is target product; base1 is base solution; base2 is inorganic base aqueous solution.

2. The fully continuous flow process for the preparation of valproic acid according to claim 1, characterized in that, In step (1): the acetoacetic ester is one of acetoacetic methyl ester, acetoacetic ethyl ester, acetoacetic propyl ester and acetoacetic tert-butyl ester; the organic solvent is any one of alcohol, chlorinated hydrocarbon, alkane and aromatic hydrocarbon; the catalyst is one of quaternary ammonium salt, polyethylene glycol, crown ether and Tween; the allyl chloride is one of allyl bromide, allyl chloride and allyl iodide; the base solution is one of triethylamine, pyridine, piperidine, sodium methoxide, sodium ethoxide, sodium propoxide, sodium tert-butoxide, potassium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide or potassium carbonate.

3. The fully continuous flow process for the preparation of valproic acid according to claim 2, characterized in that, In step (1): the flow ratio of the base solution and the acetoacetic ester delivered into the first reactor is controlled so that the molar ratio of acetoacetic ester, base solution, allyl halide and catalyst is 1:(1.0-5.0):(2.0-5.0):(0.01-0.5); the temperature in the first reactor is controlled to be 20-150℃; the pressure in the first reactor is controlled to be 0-20 bar; and the residence time of the mixed reactants in the first reactor is 0.1-60 minutes.

4. The fully continuous flow process for the preparation of valproic acid according to claim 3, characterized in that, In step (2), the solvent removal device is an on-line continuous solvent recovery device.

5. The fully continuous flow process for the preparation of valproic acid according to claim 4, characterized in that, In step (3): The organic base is one of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide or potassium tert-butoxide; The temperature in the second reactor is controlled at 20-200°C; the pressure in the second reactor is controlled at 0-50 bar; and the residence time of the mixed reaction materials in the second reactor is 0.1-20 minutes.

6. The fully continuous flow process for the preparation of valproic acid according to claim 5, characterized in that, In step (4): The catalyst pre-filled in the third reactor, i.e. a fixed bed reactor, is one of palladium-carbon, platinum-carbon or Raney nickel; The temperature in the third reactor is controlled at 0-150°C; the pressure in the third reactor is controlled at 0-100 bar; and the residence time of the mixed reaction materials in the third reactor is 0.1-20 minutes.

7. The fully continuous flow process for the preparation of valproic acid according to claim 6, characterized in that, In step (5): The inorganic base is one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution or potassium carbonate aqueous solution; The temperature in the fourth reactor is controlled at 20-200°C; the pressure in the fourth reactor is controlled at 0-50 bar; and the residence time of the mixed reaction materials in the fourth reactor is 0.1-20 minutes.

8. The fully continuous flow process for the preparation of valproic acid according to one of claims 1 to 7, characterized in that, The first to fifth reactors in the continuous flow are any of dynamic tubular reactors, tubular reactors or plate reactors; and the first to fifth mixers are any of static mixers, T-type mixers, Y-type mixers, cross-type mixers, coaxial flow mixers or flow focusing mixers.

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