Continuous flow preparation method of side-bond biotin valproic acid

Abstract

The invention relates to the technical field of organic chemical engineering, provides a continuous flow preparation method of a biotin valeric acid side chain, and solves the problems of long reaction time, large potential safety hazard, high energy consumption and low efficiency of a traditional intermittent kettle type synthesis mode. The method comprises the following steps: simultaneously conveying an organic solution of sodium alkoxide and a solution containing malonate, a chloride and a catalyst into a mixer, then feeding into a reactor 1, carrying out continuous alkylation reaction, feeding an effluent reaction solution 1 into a continuous filtering device for desalting, and recovering a solvent from a filtrate through a continuous solvent recovery device; continuously conveying a high-boiling product into a reactor 2 for decarboxylation reaction; mixing the effluent reaction liquid 2 with a sodium hydroxide aqueous solution through a mixer, and then conveying the mixture into a reactor 3 for continuous hydrolysis reaction; mixing the outflowing reaction liquid 3 with a hydrochloric acid aqueous solution through a mixer, conveying the mixture into a reactor 4 for continuous acidification, and finally performing continuous extraction separation to obtain a target product.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical engineering, and in particular to a continuous flow preparation method of valproic acid with side chain biotin. Background Art

[0002] Valeric acid compounds are important fine chemical intermediates that can be used to synthesize biotin or the anti-epileptic drug sodium valproate, and have broad application prospects in the pharmaceutical and chemical industries. The structural formula of valeric acid is shown in formula (I):

[0003]

[0004] European patent EP84377 discloses a method for constructing a biotin valeric acid side chain by a wittig reaction, and the triphenylphosphine oxide produced by the reaction is difficult to separate. Chinese patent CN144522A9 discloses a method for constructing a biotin valeric acid side chain by a Grignard reagent, which requires active metal magnesium, and carbon dioxide gas participates in the reaction, which brings great safety hazards to production. U.S. Patent US4127604A discloses a method for synthesizing valproic acid using cyanoacetate as a raw material. Although the raw material is easy to obtain, sodium metal is used, and a large amount of nitrogen dioxide is produced when the cyanide group is hydrolyzed, which is not suitable for industrialization. US5856569A discloses a method for synthesizing valproic acid using acetoacetate as a raw material, which uses a large amount of bromopropane, has a low yield, and is not suitable for industrial production. Wu Changzeng (Synthesis of Sodium Valproate, Chemical Engineer, 2015, 29 (8), 10-15) reported a method for preparing valproic acid using diethyl malonate as a raw material, which uses expensive reagents and has high production costs. Summary of the invention

[0005] In order to overcome the shortcomings of the traditional intermittent reactor synthesis method, such as long reaction time, great safety hazards, high energy consumption and low efficiency, the present invention provides a continuous flow preparation method for biotin valeric acid side chain, which has low raw material cost, shortened reaction time, significantly improved automation and efficiency of the process, greatly reduced energy consumption, greatly improved safety, and easy industrial application.

[0006] The fully continuous flow preparation method provided by the present invention uses a reaction system consisting of a mixer and a continuous flow reactor connected in sequence, and the specific steps of the method are:

[0007] (1) The organic solution of sodium alcoholate and the solution containing malonate, chlorinated product and catalyst are simultaneously transported to a mixer and then enter a reactor 1 for continuous alkylation reaction to obtain a reaction solution 1;

[0008] (2) the reaction solution 1 discharged from step (1) enters a continuous filtration device for desalination, and the filtrate is passed through a continuous solvent recovery device to recover the solvent;

[0009] (3) the high boiling product discharged in step (2) is continuously transported to the reactor 2 for decarboxylation reaction;

[0010] (4) the reaction solution 2 discharged from step (3) is mixed with the sodium hydroxide aqueous solution in a mixer and then transported to a reactor 3 for continuous hydrolysis reaction;

[0011] (5) The reaction solution 3 discharged from step (4) is mixed with the hydrochloric acid aqueous solution in a mixer and then transported to a reactor 4 for continuous acidification, and finally the product is obtained by continuous extraction and separation;

[0012] The chemical reaction formula is:

[0013]

[0014] Wherein, the R group is a C1-C4 alkyl group, R1 is H, a C3 straight chain alkyl group or R2 is H, C3 is a straight-chain alkyl group, the malonate is a compound represented by formula (II); the disubstituted malonate is a compound represented by formula (III), the valerate is a compound represented by formula (IV), and formula (I) is the target product.

[0015] Preferably, the sodium alkoxide in step (1) is one of sodium methoxide, sodium ethoxide and sodium propoxide; the organic solvent is any one of alcohols; further preferably, the sodium alkoxide is sodium methoxide or sodium ethoxide, and the alcohol solvent is methanol, ethanol or propanol.

[0016] Preferably, the catalyst in step (1) is one of a quaternary ammonium salt, polyethylene glycol, a crown ether, and propyl bromide. More preferably, the catalyst is a quaternary ammonium salt or a crown ether.

[0017] Preferably, the flow ratio of the sodium alcoholate solution and the malonate delivered to the continuous flow reactor in step (1) is controlled so that the molar ratio of the malonate to the sodium alcoholate, the chlorinated product, and the catalyst is in the range of 1:(2.0-5.0):(2.0-5.0):(0.01-0.5), and further preferably, the molar ratio of the malonate to the sodium alcoholate, the chloropropane, and the catalyst is in the range of 1:(1.0-3.0):(1.0-3.0):(0.01-0.2).

[0018] Preferably, the temperature in the continuous flow reactor described in step (1) is controlled within the range of 20-150°C; the pressure in the reactor is controlled within the range of 0-20 bar; the residence time of the mixed reaction materials in the reactor is 0.1-60 minutes, and more preferably, the temperature is controlled within the range of 20-100°C, the pressure is controlled within the range of 0-10 bar, and the residence time is 0.1-30 minutes.

[0019] Preferably, the desalting device in step (2) is an online continuous filtration device; the desolventizing device is an online continuous solvent recovery device.

[0020] Preferably, the temperature in the continuous flow reactor described in step (3) is controlled within the range of 150-250°C; the pressure in the reactor is controlled within the range of 0-50 bar; the residence time of the mixed reaction materials in the reactor is 0.1-20 minutes, and more preferably, the temperature is controlled within the range of 160-220°C, the pressure is controlled within the range of 20-30 bar, and the residence time is 0.1-15 minutes.

[0021] Preferably, the temperature in the continuous flow reactor described in step (4) is controlled within the range of 0-150°C; the pressure in the reactor is controlled within the range of 0-20 bar; the residence time of the mixed reaction materials in the reactor is 0.1-20 minutes, and more preferably, the temperature is controlled within the range of 30-120°C, the pressure is controlled within the range of 5-15 bar, and the residence time is 0.1-15 minutes.

[0022] Preferably, the temperature in the continuous flow reactor described in step (5) is controlled within the range of 0-50°C; the residence time of the mixed reaction materials in the reactor is 0.1-10 minutes, and more preferably, the temperature is controlled within the range of 0-30°C, and the residence time is 0.1-5 minutes.

[0023] Preferably, the continuous flow reactor described in steps (1), (2), (3), (4) and (5) is a dynamic tubular reactor, a tubular reactor or a plate reactor, and more preferably the continuous flow reactor is a dynamic tubular reactor or a tubular reactor.

[0024] The mixer described in steps (1), (2), (3), (4) and (5) is any one of a static mixer, a T-type mixer, a Y-type mixer, a cross-type mixer, a coaxial flow mixer or a flow focusing mixer, and more preferably the mixer is a Y-type mixer, a coaxial flow mixer or a flow focusing mixer.

[0025] The method for continuously preparing valproic acid (I) using a continuous flow reaction system can conveniently realize industrial large-scale production of valproic acid through a multi-channel parallel amplification strategy.

[0026] Beneficial effects:

[0027] The method for preparing compound (I) using a continuous flow reaction system comprising a mixer and a continuous flow reactor connected in sequence proposed in the present invention has the following advantages over the synthesis method using a traditional batch reactor:

[0028] The continuous flow reaction system has excellent mass transfer, heat transfer and material molecular mixing properties, which greatly shortens the reaction time and improves the reaction efficiency from several days in traditional intermittent kettle reactions to tens of minutes, greatly improving the danger of kettle high-temperature reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The figure is a schematic diagram of the reaction flow of an embodiment of the present invention. DETAILED DESCRIPTION

[0031] In order to explain the technical content, structural features, achieved purpose and effect of the technical solution in detail, the following is further described in conjunction with specific embodiments and accompanying drawings. This embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation method and specific operation process are given, but the protection scope of the present invention is not limited to the following embodiments.

[0032] The structure of the reaction system used in the embodiment is as shown in the attached Figure 1 Shown

[0033] Its working process is:

[0034] The feed pump simultaneously delivers the organic solution of sodium alcoholate and the solution containing malonate, chlorinated product and catalyst to the mixer and then enters the reactor 1 for continuous alkylation reaction; the outflowing reaction liquid 1 enters the continuous filtration device for desalination, and the filtrate is recycled through the continuous solvent recovery device; the high-boiling product is continuously transported to the reactor 2 for decarboxylation reaction; the outflowing reaction liquid 2 is mixed with the sodium hydroxide aqueous solution through the mixer and then transported to the reactor 3 for continuous hydrolysis reaction; the outflowing reaction liquid 3 is mixed with the hydrochloric acid aqueous solution through the mixer and then transported to the reactor 4 for continuous acidification, and finally the target compound is obtained through continuous extraction and separation.

[0035] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0036] Example 1: Continuous Flow Preparation of Biotin

[0037] The methanol solution of sodium methoxide and the methanol solution containing methyl malonate, biotin chloride precursor and tetrapropylammonium bromide were respectively and simultaneously transported to the dynamic tubular reactor 1 (reaction volume was 200 ml, channel diameter was 10 mm) by a plunger pump, the flow ratio of the pump was adjusted so that the molar ratio of methyl malonate to sodium methoxide, biotin chloride precursor and tetrapropylammonium bromide was 1:1.2:1.1:0.05, the temperature of the reaction solution was controlled to 85°C, the residence time was 15 minutes, the back pressure of the system was 10 bar, the outflowing reaction solution entered the continuous filtration device for desalination, the filtrate was transported to the continuous solvent recovery device for methanol recovery by a peristaltic pump, the high boiling product was continuously transported to the tubular reactor 2 (reaction volume was 200 ml, channel diameter was 10 mm) by a plunger pump, the temperature of the reaction solution was controlled to 200°C, the residence time was 10 minutes, the outflowing reaction solution was mixed with 5M sodium hydroxide aqueous solution through a mixer and then transported to the tubular reactor 3 (reaction volume was 100 m l, channel diameter 10mm), adjust the flow ratio of the pump so that the molar ratio of the decarboxylation product to sodium hydroxide is 1:1.1, the temperature of the reaction solution is controlled to 80°C, the residence time is 8 minutes, the system back pressure is 10bar, the outflowing reaction solution is mixed with a 6M hydrochloric acid aqueous solution through a mixer and then transported to a tubular reactor 4 (reaction volume is 30ml, channel diameter is 10mm), the temperature is controlled to 30°C, the residence time is 3 minutes, and finally pure biotin is obtained by continuous extraction and separation, with a total yield of 82% and a purity of 99.6%.

[0038] Example 2: Continuous Flow Preparation of Biotin

[0039] This example is the same as Example 1, the only difference being that the raw material used in this example is diethyl malonate, and the obtained biotin has a yield of 85% and a purity of 99.5%.

[0040] Example 3: Continuous Flow Preparation of Valproic Acid

[0041] The methanol solution of sodium methoxide and the methanol solution containing methyl malonate, chloropropane and tetrapropylammonium bromide were simultaneously transported to the dynamic tubular reactor 1 (reaction volume was 200 ml, channel diameter was 10 mm) by plunger pumps, the flow ratio of the pump was adjusted so that the molar ratio of methyl malonate to sodium methoxide, chloropropane and tetrapropylammonium bromide was 1:2.3:2.1:0.05, the temperature of the reaction solution was controlled to 85°C, the residence time was 15 minutes, the back pressure of the system was 10 bar, the outflowing reaction solution entered the continuous filtration device for desalination, the filtrate was transported to the continuous solvent recovery device for methanol recovery by a peristaltic pump, the high boiling product was continuously transported to the tubular reactor 2 (reaction volume was 200 ml, channel diameter was 10 mm) by a plunger pump, the temperature of the reaction solution was controlled to 200°C, the residence time was 10 minutes, the outflowing reaction solution was mixed with 5M sodium hydroxide aqueous solution through a mixer and then transported to the tubular reactor 3 (reaction volume was 100 m l, channel diameter 10mm), adjust the flow ratio of the pump so that the molar ratio of the decarboxylation product to sodium hydroxide is 1:1.1, the temperature of the reaction solution is controlled to 80°C, the residence time is 8 minutes, the system back pressure is 10bar, the outflowing reaction solution is mixed with a 6M hydrochloric acid aqueous solution through a mixer and then transported to a tubular reactor 4 (reaction volume is 30ml, channel diameter is 10mm), the temperature is controlled to 30°C, the residence time is 3 minutes, and finally pure valproic acid is obtained by continuous extraction and separation, with a total yield of 81% and a purity of 99.3%.

[0042] Example 4: Continuous Flow Preparation of Valproic Acid

[0043] This example is the same as Example 3, the only difference being that the reactor used in this example is a plate reactor with a volume of 200 ml and an inner diameter of 4 mm. The yield of valproic acid obtained is 88% and the purity is 99.6%.

[0044] Example 5: Continuous Flow Preparation of Valproic Acid

[0045] This example is the same as Example 3, the only difference being that in this example, sodium alkoxide is replaced by sodium propoxide, and the yield of valproic acid obtained is 80% and the purity is 99.8%.

[0046] It should be noted that, although the above embodiments have been described in this article, the patent protection scope of the present invention is not limited thereby. Therefore, based on the innovative concept of the present invention, changes and modifications made to the embodiments described herein, or equivalent structures or equivalent process transformations made using the contents of the present specification and drawings, directly or indirectly applying the above technical solutions to other related technical fields are all included in the patent protection scope of the present invention.

Claims

1. A continuous flow preparation method of biotin valproic acid with side bonds, characterized in that: A reaction system consisting of a mixer and a continuous flow reactor connected in sequence is used, and the method comprises the following specific steps: (1) The organic solution of sodium alcoholate and the solution containing malonate, chlorinated product and catalyst are simultaneously transported to a mixer and then enter a continuous flow reactor 1 for continuous alkylation reaction to obtain a reaction solution 1; (2) the reaction solution 1 discharged from step (1) enters an online continuous filtration device for desalination, and the filtrate is passed through an online continuous solvent recovery device to recover the solvent; (3) the high boiling product discharged in step (2) is continuously transported to a continuous flow reactor 2 for decarboxylation reaction to obtain a reaction solution 2; (4) the reaction solution 2 discharged from step (3) is mixed with the sodium hydroxide aqueous solution in a mixer and then transported to a continuous flow reactor 3 for continuous hydrolysis reaction to obtain a reaction solution 3; (5) The reaction solution 3 discharged from step (4) is mixed with the hydrochloric acid aqueous solution in a mixer and then transported to a continuous flow reactor 4 for continuous acidification, and finally the product is obtained by continuous extraction and separation; The chemical reaction formula is: Wherein, the R group is a C1-C4 alkyl group, R1 is H or a C3 straight chain alkyl group or R2 is H or a C3 straight-chain alkyl group, the malonate is a compound represented by formula (II); the disubstituted malonate is a compound represented by formula (III), the valerate is a compound represented by formula (IV), and formula (I) is the target product.

2. The continuous flow preparation method of a biotinylated valproic acid with side bonds according to claim 1, characterized in that: The sodium alcoholate in step (1) is one of sodium methoxide, sodium ethoxide or sodium propoxide; and the organic solution is any one of alcohols.

3. The continuous flow preparation method of a biotinylated valproic acid with side bonds according to claim 1, characterized in that: The catalyst in step (1) is one of quaternary ammonium salt, polyethylene glycol, crown ether or propyl bromide.

4. The continuous flow preparation method of a biotinylated valproic acid with side bonds according to claim 1, characterized in that: The flow ratio of the sodium alcoholate solution and the malonate delivered to the continuous flow reactor 1 is controlled in step (1) so that the molar ratio of the malonate, the sodium alcoholate, the chlorinated product and the catalyst is in the range of 1:2.0-5.0:2.0-5.0:0.01-0.

5.

5. The continuous flow preparation method of a biotinylated valproic acid with side bonds according to claim 1, characterized in that: The temperature in the continuous flow reactor 1 described in step (1) is controlled within the range of 20-150° C.; the pressure in the continuous flow reactor 1 is controlled within the range of 0-20 bar; and the residence time of the mixed reaction materials in the continuous flow reactor 1 is 0.1-60 minutes.

6. The continuous flow preparation method of a biotinylated valproic acid with side bonds according to claim 1, characterized in that: The temperature in the continuous flow reactor 2 described in step (3) is controlled within the range of 150-250° C.; the pressure in the continuous flow reactor 2 is controlled within the range of 0-50 bar; and the residence time of the mixed reaction materials in the continuous flow reactor 2 is 0.1-20 minutes.

7. The continuous flow preparation method of a biotinylated valproic acid with side bonds according to claim 1, characterized in that: The temperature in the continuous flow reactor 3 described in step (4) is controlled within the range of 0-150° C.; the pressure in the continuous flow reactor 3 is controlled within the range of 0-20 bar; and the residence time of the mixed reaction materials in the continuous flow reactor 3 is 0.1-20 minutes.

8. The continuous flow preparation method of a biotinylated valproic acid with side bonds according to claim 1, characterized in that: The temperature in the continuous flow reactor 4 described in step (5) is controlled within the range of 0-50° C.; the residence time of the mixed reaction materials in the continuous flow reactor 4 is 0.1-10 minutes.

9. A continuous flow preparation method of biotin valproic acid with side bonds according to any one of claims 1 to 8, characterized in that: The continuous flow reactor 1 described in step (1), the continuous flow reactor 2 described in step (3), the continuous flow reactor 3 described in step (4) and the continuous flow reactor 4 described in step (5) are all dynamic tubular reactors, tubular reactors or plate reactors; The mixer is any one of a static mixer, a T-type mixer, a Y-type mixer, a cross mixer, a coaxial flow mixer or a flow focusing mixer.

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