Citicoline impurity removal and purification device and method

Abstract

The invention belongs to the technical field of impurity removal and purification equipment for drug synthesis, and particularly relates to a citicoline impurity removal and purification device and method.The impurity removal and purification device comprises a desalination column passing mechanism and a refining mechanism, the desalination column passing mechanism comprises a desalination unit and a column passing unit, and a neutralization kettle in the desalination unit is connected with a hydrochloric acid storage tank; the upper surface of the neutralization kettle is provided with a citicoline intermediate 1 concentrated solution inlet, the lower surface of the neutralization kettle is connected with the desalination kettle through a fine filtration unit, the lower surface of the desalination kettle is connected with the inlet end of the nanofiltration membrane, the outlet end of the nanofiltration membrane is divided into two paths, one path is connected with the upper surface of the desalination kettle, and the other path is connected with the left side of the upper surface of the transfer tank. The lower part of the right surface of the transfer tank is connected with a column passing unit; a decolorizing kettle in the refining mechanism is connected with an outlet of the column passing unit through a refined filtration unit. According to the method, the citicoline is subjected to desalination, impurity removal and adsorption decoloration treatment, the purity of the citicoline can be effectively improved, the treatment process is simple and easy to operate, the treatment cost is low, and industrial production can be realized.

Description

Technical Field

[0001] The invention belongs to the technical field of impurity removal and purification equipment for drug synthesis, and specifically relates to a device and method for impurity removal and purification of citicoline. Background Art

[0002] Citicoline is used as a pharmaceutical intermediate, medical raw material, scientific research reagent, etc. Citicoline is a brain metabolism activator, a derivative of nucleic acid, and a major coenzyme for the synthesis of lecithin. In clinical practice, it is mainly used to treat sequelae of the nervous system caused by craniocerebral injury and cerebrovascular accident.

[0003] In order to improve the use effect of citicoline, citicoline is generally subjected to impurity removal and purification treatment to improve the purity of citicoline, but the existing citicoline impurity removal and purification treatment process is complicated, the treatment cost is high, and it is difficult to achieve industrial production. Therefore, in order to overcome the above-mentioned technical problems and defects, a citicoline impurity removal and purification device and method are proposed. Summary of the invention

[0004] The purpose of the present invention is to overcome the deficiencies of the prior art and to provide a device and method for removing impurities and purifying citicoline.

[0005] The object of the present invention is achieved in that:

[0006] A citicoline impurity removal and purification device comprises a desalting column mechanism and a refining mechanism, wherein the desalting column mechanism comprises a desalting unit and a column unit, wherein the desalting unit comprises a hydrochloric acid storage tank, a neutralization kettle and a desalting kettle, wherein the neutralization kettle is connected to the hydrochloric acid storage tank via a pipeline and a feeding pump, an inlet for a citicoline intermediate 1 concentrate is arranged on the upper surface of the neutralization kettle, and the lower surface of the neutralization kettle is connected to the desalting kettle via a pipeline and a fine filtration unit, a cooling jacket is arranged on the outer side of the desalting kettle, the lower surface of the desalting kettle is connected to an inlet end of a nanofiltration membrane via a pipeline, and the outlet end of the nanofiltration membrane branches into two paths, wherein one path is connected to the upper surface of the desalting kettle via a pipeline, and the other path is connected to the left side of the upper surface of a transfer tank via a pipeline, a cooling jacket is arranged on the outer side of the transfer tank, the lower part of the right surface of the transfer tank is connected to the inlet end of a feeding pump via a pipeline, the outlet end of the feeding pump is connected to the column unit via a pipeline, and the outlet of the column unit is an outlet for a crude citicoline product;

[0007] The refining mechanism comprises a decolorizing kettle, which is connected to a fine filtration unit through a pipeline, which is connected to a crude citicoline outlet through a pipeline, a solid feeder is connected to the upper surface of the decolorizing kettle, a condensation jacket is provided on the outer side of the decolorizing kettle, a pipeline connected to the lower surface of the decolorizing kettle branches into two paths, one of which is connected to a nanofiltration membrane through a pipeline, and the other is connected to a suction filtration tank through a pipeline, a waste solid outlet is provided on the upper surface of the suction filtration tank, the lower surface of the suction filtration tank is connected to a crystallization kettle through a pipeline, the upper surface of the crystallization kettle is connected to a methanol-acetone mixed solution storage tank through a pipeline and a feeding pump, and a condensation jacket is provided on the outer side of the crystallization kettle. A heating jacket is provided, the upper surface of the crystallization kettle is connected to the inlet end of the condenser through a pipeline, the outlet end of the condenser is connected to the mixed liquid receiving tank through a pipeline, the pipeline connected to the lower surface of the mixed liquid receiving tank branches into two paths, one of which is connected to the upper surface of the crystallization kettle through a pipeline, and the other is connected to the sewage outlet through a pipeline, the lower surface of the crystallization kettle is connected to the centrifuge through a pipeline, the liquid outlet end of the centrifuge is connected to the upper surface of the crystallization kettle through a pipeline, the solid outlet of the centrifuge is connected to the double cone dryer through a pipeline and a citicoline wet product transport unit, and the outlet of the double cone dryer is connected to the citicoline finished product transport unit through a pipeline.

[0008] Furthermore, the structural formula of the citicoline intermediate 1 is as follows:

[0009]

[0010] Furthermore, the column passing unit includes a first anode column and a second anode column, the outlet end of the feeding pump is connected to the upper surface of the first anode column through a pipeline, the lower surface of the first anode column is connected to the upper surface of the second anode column through a pipeline, the pipeline connected to the lower surface of the second anode column is respectively connected to the first cathode column group and the second cathode column group, the first cathode column group and the second cathode column group are arranged in parallel, and the outlets of the first cathode column group and the second cathode column group are combined into a crude citicoline outlet.

[0011] Furthermore, the first cathode column group includes three cathode columns distributed in series, and the second cathode column group includes three cathode columns distributed in series.

[0012] Furthermore, chilled water and circulating water flow in the cooling jacket, the cooling jacket and the condensing jacket, and steam flows in the heating jacket.

[0013] Furthermore, activated carbon is added into the solid feeder.

[0014] Furthermore, the concentration of hydrochloric acid stored in the hydrochloric acid storage tank is 36%.

[0015] The present invention also discloses a method for using the citicoline impurity removal and purification device, comprising the following steps:

[0016] (1) The concentrated solution of citicoline intermediate 1 enters the neutralization kettle, the feeding pump is turned on, 36% hydrochloric acid in the hydrochloric acid storage tank enters the neutralization kettle, and the pH is adjusted to between 4.7 and 5.0. After the pH value is stable, the bottom valve of the neutralization kettle is opened, the material in the kettle is finely filtered into the desalting kettle, and the cooling jacket outside the desalting kettle is turned on to cool the temperature to 20-25° C. and temporarily stored;

[0017] (2) Open the bottom valve of the desalination kettle, and the materials in the kettle enter the nanofiltration membrane for sodium filtration desalination. Samples are taken from the nanofiltration membrane outlet every hour to monitor the conductivity and salinity. When the conductivity drops to 5ms / cm and the salinity drops to less than 3ms / cm, the desalination is terminated;

[0018] (3) The material after nanofiltration desalination enters the transfer tank, and the cooling jacket on the outside of the transfer tank is turned on to control the temperature to 15-25°C;

[0019] (4) Open the bottom valve of the transfer tank and the feeding pump, and load the sample at a speed of 500-600L per hour, and load the first anode column and the second anode column in turn. When there is material at the outlet of the second anode column, transfer it to the first cathode column group and the second cathode column group. After the anode column is loaded with sample, wash the column with pure water at 600L per hour until the concentration at the outlet of the anode column is lower than 1g / L. The anode column can be activated and cleaned for use;

[0020] (5) Open the first eluent valve of the first cathode column group and the second cathode column group, pump pure water and 0.1% formic acid solution into the cathode column at a rate of 500 L per hour, monitor the reaction liquid at the end of the cathode column group during the elution process, and monitor that the material concentration is between 20±5 g / L through the crude citicoline outlet to the fine filtration unit, and then enter the decolorization kettle after fine filtration;

[0021] (6) Open the chilled water of the condensing jacket outside the decolorization kettle, control the temperature at 15-25° C., open the discharge valve at the bottom of the tank, and allow the reaction liquid to enter the nanofiltration membrane for sodium filtration concentration. The concentrated liquid after nanofiltration concentration is refluxed into the decolorization kettle, and activated carbon is added to the decolorization kettle through a solid feeder. After the activated carbon is decolorized, the citicoline concentrate enters the suction filtration tank for filtration. The filtered activated carbon is discharged through the waste solid outlet, and the filtered citicoline concentrate enters the crystallization kettle;

[0022] (7) Turn on the feeding pump, the methanol-acetone mixed liquid in the methanol-acetone mixed liquid storage tank enters the crystallization kettle, turn on the steam of the heating jacket outside the crystallization kettle, heat and concentrate the citicoline concentrate, and the distillate after heating and concentration enters the mixed liquid receiving tank after the methanol-acetone is condensed by the condenser, and then flows back to the crystallization kettle, cools down and crystallizes, and enters the centrifuge for centrifugal separation, and the distillate is condensed by the condenser for more than three times and discharged through the sewage outlet at the bottom of the mixed liquid receiving tank;

[0023] (8) The mother liquor separated by centrifugation is returned to the crystallization kettle for recycling, and the solid separated by centrifugation enters the double cone dryer through the citicoline wet product transfer unit. The dried citicoline finished product enters the finished product packaging and storage process through the citicoline finished product transfer unit.

[0024] Further, after continuously treating three batches of reaction liquid, the first anode column and the second anode column are activated by alternately adopting the bottom-in-top-out / top-in-bottom-out activation method, and the activation steps are as follows:

[0025] (1) Pumping 3% NaOH solution into the first anode column and the second anode column, closing the inlet and outlet valves after loading, and soaking for 4 to 8 hours, wherein the amount of 3% NaOH solution used is 1.5 to 2 times the volume of the resin filled in the anode column;

[0026] (2) After the alkaline solution washing and soaking is completed, the bottom valve of the anode column is opened, and tap water is pumped into the anode column. The washing is stopped when the pH value at the outlet of the bottom valve of the anode column is 8-9, and the washing liquid is collected and barreled to the sewage treatment station;

[0027] (3) After the tap water solution washing is completed, open the bottom valve of the anode column and pump 3% hydrochloric acid solution into the anode column. After the loading is completed, close the inlet and outlet valves and soak for more than 4 hours. The amount of 3% hydrochloric acid solution is 1.5 to 2 times the volume of the resin filled in the anode column;

[0028] (4) After the hydrochloric acid solution washing and soaking is completed, 5 to 6 hours before the column is loaded, open the bottom valve of the anode column and pump pure water into the anode column. Wash until the pH value at the outlet of the bottom valve of the anode column is 5 to 6 and stop. Collect the washing liquid and put it into a barrel and send it to the sewage treatment station.

[0029] Furthermore, after continuously treating three batches of reaction liquid, the first cathode column group and the second cathode column group are activated by alternately using the bottom-in-top-out / top-in-bottom-out activation method, and the activation steps are as follows:

[0030] (1) Pump 3% hydrochloric acid solution into the cathode column, close the inlet and outlet valves after loading, and soak for 4 to 8 hours. The amount of 3% hydrochloric acid solution used is 1.5 to 2 times the volume of the resin filled in the cathode column;

[0031] (2) After the hydrochloric acid solution washing and soaking is completed, the bottom valve of the cathode column is opened, and pure water is pumped into the cathode column. The washing is stopped when the pH value at the outlet of the bottom valve of the cathode column is 5 to 6. The washing liquid is collected and barreled and sent to the sewage treatment station;

[0032] (3) After washing with pure water solution, open the bottom valve of the cathode column and pump 3% NaOH solution into the cathode column. After loading, close the inlet and outlet valves and soak for more than 4 hours. The amount of 3% NaOH solution is 1.5 to 2 times the volume of the resin filled in the anode column.

[0033] (4) After the alkaline solution washing and soaking is completed, 5 to 6 hours before the column is loaded, open the cathode column bottom valve and pump pure water into the cathode column. Wash until the pH value at the cathode column bottom valve outlet is 8 to 9 and stop. Collect the washing liquid and put it into a barrel and send it to the sewage treatment station.

[0034] The reaction equation of citicoline is divided into two steps, wherein the first step is the reaction of 5'-cytidylic acid with DCC (N,N'-dicyclohexylcarboximide) and morpholine in a methanol solution to generate an intermediate 1, and the second step is the desalting, column loading, elution, and concentration of the intermediate 1 to obtain a citicoline concentrate. The specific reaction equation is as follows:

[0035]

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] According to the invention, 5'-cytidylic acid reacts with DCC and morpholine in a methanol solution to generate an intermediate 1, and the intermediate 1 is desalted, loaded onto a column, eluted and concentrated to obtain a citicoline concentrate. The citicoline concentrate is decolorized and filtered with activated carbon, and then methanol and acetone are added for crystallization. The citicoline wet product is cooled and centrifuged to obtain a citicoline product, and the finished product is dried. In the preparation process, an impurity removal and purification device is used to remove impurities and purify the citicoline, a nanofiltration membrane is used to desalt the citicoline, a cation column is used to remove impurities from the citicoline, and activated carbon is used to adsorb and decolorize the citicoline, so that the purity of the citicoline can be effectively improved, and the impurity removal and purification process is simple and easy to operate, with low processing cost, and industrial production can be realized. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 It is a schematic structural diagram of the desalting column mechanism in the citicoline impurity removal and purification device of the present invention.

[0039] Figure 2 It is a schematic diagram of the structure of the refining mechanism in the citicoline impurity removal and purification device of the present invention.

[0040] Figure 3 The present invention is a process flow chart of the production of citicoline.

[0041] In the figure: 1-hydrochloric acid storage tank, 2-feeding pump, 3-inlet of concentrated solution of citicoline intermediate 1, 4-neutralization kettle, 5-fine filtration unit, 6-desalting kettle, 7-cooling jacket, 8-nanofiltration membrane, 9-transfer tank, 10-cooling jacket, 11-feeding pump, 12-first anode column, 13-second anode column, 14-first cathode column group, 1401-cathode column, 15-second cathode column group, 1501-cathode column, 16-citicoline crude product outlet, 17 -fine filtration unit, 18-solid feeder, 19-decolorization kettle, 20-condensation jacket, 21-nanofiltration membrane, 22-suction filtration tank, 23-waste solid outlet, 24-methanol acetone mixed liquid storage tank, 25-feeding pump, 26-crystallization kettle, 27-heating jacket, 28-condenser, 29-mixed liquid receiving tank, 30-wastewater outlet, 31-centrifuge, 32-cytidic acid choline wet product transport unit, 33-double cone dryer, 34-cytidic acid choline finished product transport unit. DETAILED DESCRIPTION

[0042] The phosphorus choline impurity removal and purification device of the present invention is described in more detail below with reference to the accompanying drawings and through specific embodiments.

[0043] In the description of the present invention, it is necessary to understand that the terms "upper", "lower", "front", "back", "left", "right", "top", "bottom", "inside", "outside", etc., indicating the orientation or position relationship are based on the orientation or position relationship shown in the drawings, and are only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as a limitation on the present invention.

[0044] See also Figures 1-2 A citicoline impurity removal and purification device comprises a desalting column mechanism and a refining mechanism, wherein the desalting column mechanism comprises a desalting unit and a column unit, wherein the desalting unit comprises a hydrochloric acid storage tank 1, a neutralization kettle 4 and a desalting kettle 6, wherein the neutralization kettle 4 is connected to the hydrochloric acid storage tank 1 through a pipeline and a feeding pump 2, wherein an inlet for a concentrated solution of a citicoline intermediate 1 is arranged on the upper surface of the neutralization kettle 4, wherein the lower surface of the neutralization kettle 4 is connected to the desalting kettle 6 through a pipeline and a fine filtration unit 5, wherein a cooling jacket is arranged on the outer side of the desalting kettle 6 7, the lower surface of the desalting kettle 6 is connected to the inlet end of the nanofiltration membrane 8 through a pipeline, and the outlet end of the nanofiltration membrane 8 branches into two paths, one of which is connected to the upper surface of the desalting kettle 6 through a pipeline, and the other is connected to the left side of the upper surface of the transfer tank 9 through a pipeline. The outer side of the transfer tank 9 is provided with a cooling sleeve 10, and the lower part of the right surface of the transfer tank 9 is connected to the inlet end of the feeding pump 11 through a pipeline, and the outlet end of the feeding pump 11 is connected to the column unit through a pipeline, and the outlet of the column unit is the crude citicoline outlet 16;

[0045] See also Figure 2The refining mechanism includes a decolorizing kettle 19, which is connected to a fine filtration unit 17 through a pipeline, and the fine filtration unit 17 is connected to a crude citicoline outlet 16 through a pipeline. A solid feeder 18 is connected to the upper surface of the decolorizing kettle 19, and a condensation jacket 20 is provided on the outer side of the decolorizing kettle 19. The pipeline connected to the lower surface of the decolorizing kettle 19 branches into two paths, one of which is connected to a nanofiltration membrane 21 through a pipeline, and the other is connected to a suction filtration tank 22 through a pipeline. A waste solid outlet 23 is provided on the upper surface of the suction filtration tank 22, and the lower surface of the suction filtration tank 22 is connected to a crystallization kettle 26 through a pipeline. The upper surface of the crystallization kettle 26 is connected to a methanol-acetone mixed liquid storage tank 24 through a pipeline and a feeding pump 25. The outer surface of the crystallization kettle 26 A heating jacket 27 is provided on the side sleeve. The upper surface of the crystallization kettle 26 is connected to the inlet end of the condenser 28 through a pipeline, and the outlet end of the condenser 28 is connected to the mixed liquid receiving tank 29 through a pipeline. The pipeline connected to the lower surface of the mixed liquid receiving tank 29 branches into two paths, one of which is connected to the upper surface of the crystallization kettle 26 through a pipeline, and the other is connected to the sewage outlet 30 through a pipeline. The lower surface of the crystallization kettle 26 is connected to the centrifuge 31 through a pipeline, and the liquid outlet end of the centrifuge 31 is connected to the upper surface of the crystallization kettle 26 through a pipeline. The solid outlet of the centrifuge 31 is connected to the double cone dryer 33 through a pipeline and a citicoline wet product transport unit 32, and the outlet of the double cone dryer 33 is connected to the citicoline finished product transport unit 34 through a pipeline.

[0046] See also Figure 1 The column passing unit includes a first anode column 12 and a second anode column 13. The outlet end of the feeding pump 11 is connected to the upper surface of the first anode column 12 through a pipeline. The lower surface of the first anode column 12 is connected to the upper surface of the second anode column 13 through a pipeline. The pipeline connected to the lower surface of the second anode column 13 is respectively connected to the first cathode column group 14 and the second cathode column group 15. The first cathode column group 14 and the second cathode column group 15 are arranged in parallel. The outlets of the first cathode column group 14 and the second cathode column group 15 are combined into a crude citicoline outlet 16.

[0047] See also Figure 1 The first cathode column group 14 includes three cathode columns 1401 distributed in series, and the second cathode column group 15 includes three cathode columns 1501 distributed in series.

[0048] See also Figures 1-2 Chilled water and circulating water flow in the cooling jacket 7 , the cooling jacket 10 and the condensing jacket 20 , and steam flows in the heating jacket 27 .

[0049] Furthermore, activated carbon is added into the solid feeder 18 .

[0050] Furthermore, the concentration of hydrochloric acid stored in the hydrochloric acid storage tank 1 is 36%.

[0051] The method for using the citicoline impurity removal and purification device comprises the following steps:

[0052] (1) The concentrated solution of the citicoline intermediate 1 enters the neutralization kettle 4, the feeding pump 2 is turned on, and the 36% hydrochloric acid in the hydrochloric acid storage tank 1 enters the neutralization kettle 4, and the pH is adjusted to between 4.7 and 5.0. After the pH value is stable, the bottom valve of the neutralization kettle 4 is opened, and the material in the kettle is finely filtered into the desalting kettle 6. The cooling jacket 7 outside the desalting kettle 6 is turned on to cool the water, and the temperature is lowered to 20-25° C. and temporarily stored;

[0053] (2) Open the bottom valve of the desalination reactor 6, and the material in the reactor enters the nanofiltration membrane 8 for sodium filtration desalination. Samples are taken from the nanofiltration membrane outlet every hour to monitor the conductivity and salinity. When the conductivity drops to 5ms / cm and the salinity drops to less than 3ms / cm, the desalination is terminated;

[0054] (3) The material after nanofiltration desalination enters the transfer tank 9, and the cooling jacket 10 outside the transfer tank 9 is turned on to cool the water and control the temperature to 15-25°C;

[0055] (4) Open the bottom valve and the feeding pump of the transfer tank 9, and load the sample at a speed of 500-600 L per hour, and load the first anode column 12 and the second anode column 13 in turn. When there is material at the outlet of the second anode column 13, transfer it to the first cathode column group 14 and the second cathode column group 15. After the anode column is loaded with sample, wash the column with pure water at 600 L per hour until the concentration at the outlet of the anode column is lower than 1 g / L. The anode column can be activated and cleaned for use;

[0056] (5) Open the first eluent valve of the first cathode column group 14 and the second cathode column group 15, and pump pure water and 0.1% formic acid solution into the cathode column at a rate of 500 L per hour. During the elution process, monitor the reaction liquid at the end of the cathode column group. Monitor the material concentration between 20±5 g / L to the fine filtration unit through the crude citicoline outlet 16, and then enter the decolorization kettle 19 after fine filtration;

[0057] (6) Open the condensing jacket 20 on the outside of the decolorizing kettle 19 to cool the water, control the temperature at 15-25° C., open the discharge valve at the bottom of the tank, and allow the reaction solution to enter the nanofiltration membrane 21 for sodium filtration concentration. The concentrated solution after nanofiltration concentration is refluxed into the decolorizing kettle 19, and activated carbon is added to the decolorizing kettle 19 through the solid feeder 18. After the activated carbon is used for decolorization, the citicoline concentrate enters the suction filtration tank 22 for filtration, and the filtered activated carbon is discharged through the waste solid outlet 23. The filtered citicoline concentrate enters the crystallization kettle 26;

[0058] (7) Turn on the feeding pump, the methanol-acetone mixed liquid in the methanol-acetone mixed liquid storage tank 24 enters the crystallization kettle 26, turn on the steam of the heating jacket 27 outside the crystallization kettle 26, heat and concentrate the citicoline concentrate, and the distillate after heating and concentration passes through the condenser 28 to condense the methanol-acetone into the mixed liquid receiving tank 29, and then flows back to the crystallization kettle 26, cools down and crystallizes, and enters the centrifuge 31 for centrifugal separation, and the distillate is condensed more than three times by the condenser 28 and discharged through the sewage outlet 30 at the bottom of the mixed liquid receiving tank 29, wherein the volume ratio of methanol to acetone in the methanol-propanol mixed liquid is 3:1-2, and the volume of methanol is 1.5 times the volume of the material in the crystallization kettle 26;

[0059] (8) The mother liquor separated by centrifugation in the centrifuge 31 is returned to the crystallization kettle 26 for recycling, and the solid separated by centrifugation enters the double cone dryer 33 through the citicoline wet product transport unit 32. The dried citicoline finished product enters the finished product packaging and storage process through the citicoline finished product transport unit 34.

[0060] Unless otherwise defined, the technical or scientific terms used herein shall have the ordinary meaning understood by a person of ordinary skill in the field to which the invention belongs. The use of "one" or "an" and other similar words in the specification and claims of this application does not necessarily indicate a quantitative limitation. "Include" or "comprises" and other similar words mean that the elements or objects appearing before the word include the elements or objects listed after the word and their equivalents, without excluding other elements or objects. "Connect" or "connected" and other similar words are not limited to physical or mechanical connections, but may include electrical connections, whether direct or indirect.

[0061] The exemplary implementation modes of the present invention are described in detail above with reference to the preferred embodiments. However, it can be understood by those skilled in the art that, without departing from the concept of the present invention, various modifications and variations can be made to the above-mentioned specific embodiments, and various combinations of the technical features and structures proposed in the present invention can be made without exceeding the protection scope of the present invention.

Claims

1. A citicoline impurity removal and purification device, comprising a desalting column mechanism and a refining mechanism, characterized in that: The desalting column mechanism comprises a desalting unit and a column unit, the desalting unit comprises a hydrochloric acid storage tank, a neutralization kettle and a desalting kettle, the neutralization kettle is connected to the hydrochloric acid storage tank through a pipeline and a feeding pump, the upper surface of the neutralization kettle is provided with a concentrated liquid inlet of citicoline intermediate 1, the lower surface of the neutralization kettle is connected to the desalting kettle through a pipeline and a fine filtration unit, the outer side of the desalting kettle is provided with a cooling jacket, the lower surface of the desalting kettle is connected to the inlet end of the nanofiltration membrane through a pipeline, the outlet end of the nanofiltration membrane branches out into two paths, one of which is connected to the upper surface of the desalting kettle through a pipeline, and the other is connected to the left side of the upper surface of the transfer tank through a pipeline, the outer side of the transfer tank is provided with a cooling jacket, the lower part of the right surface of the transfer tank is connected to the inlet end of the feeding pump through a pipeline, the outlet end of the feeding pump is connected to the column unit through a pipeline, and the outlet of the column unit is a crude citicoline outlet; The refining mechanism comprises a decolorizing kettle, which is connected to a fine filtration unit through a pipeline, which is connected to a crude citicoline outlet through a pipeline, a solid feeder is connected to the upper surface of the decolorizing kettle, a condensation jacket is provided on the outer side of the decolorizing kettle, a pipeline connected to the lower surface of the decolorizing kettle branches into two paths, one of which is connected to a nanofiltration membrane through a pipeline, and the other is connected to a suction filtration tank through a pipeline, a waste solid outlet is provided on the upper surface of the suction filtration tank, the lower surface of the suction filtration tank is connected to a crystallization kettle through a pipeline, the upper surface of the crystallization kettle is connected to a methanol-acetone mixed solution storage tank through a pipeline and a feeding pump, and a condensation jacket is provided on the outer side of the crystallization kettle. A heating jacket is provided, the upper surface of the crystallization kettle is connected to the inlet end of the condenser through a pipeline, the outlet end of the condenser is connected to the mixed liquid receiving tank through a pipeline, the pipeline connected to the lower surface of the mixed liquid receiving tank branches into two paths, one of which is connected to the upper surface of the crystallization kettle through a pipeline, and the other is connected to the sewage outlet through a pipeline, the lower surface of the crystallization kettle is connected to the centrifuge through a pipeline, the liquid outlet end of the centrifuge is connected to the upper surface of the crystallization kettle through a pipeline, the solid outlet of the centrifuge is connected to the double cone dryer through a pipeline and a citicoline wet product transport unit, and the outlet of the double cone dryer is connected to the citicoline finished product transport unit through a pipeline.

2. The citicoline impurity removal and purification device according to claim 1, characterized in that: The structural formula of the citicoline intermediate 1 is as follows:

3. The citicoline impurity removal and purification device according to claim 1, characterized in that: The column passing unit includes a first anode column and a second anode column, the outlet end of the feeding pump is connected to the upper surface of the first anode column through a pipeline, the lower surface of the first anode column is connected to the upper surface of the second anode column through a pipeline, the pipeline connected to the lower surface of the second anode column is respectively connected to the first cathode column group and the second cathode column group, the first cathode column group and the second cathode column group are arranged in parallel, and the outlets of the first cathode column group and the second cathode column group are combined into a crude citicoline outlet.

4. The citicoline impurity removal and purification device according to claim 1, characterized in that: The first cathode column group includes three cathode columns distributed in series, and the second cathode column group includes three cathode columns distributed in series.

5. The citicoline impurity removal and purification device according to claim 1, characterized in that: Chilled water and circulating water flow in the cooling jacket, the cooling jacket and the condensing jacket, and steam flows in the heating jacket.

6. The citicoline impurity removal and purification device according to claim 1, characterized in that: Activated carbon is added into the solid feeder.

7. The citicoline impurity removal and purification device according to claim 1, characterized in that: The concentration of hydrochloric acid stored in the hydrochloric acid storage tank is 36%.

8. A method for using the citicoline impurity removal and purification device according to any one of claims 1 to 7, characterized in that: The steps include: (1) The concentrated solution of citicoline intermediate 1 enters the neutralization kettle, the feeding pump is turned on, 36% hydrochloric acid in the hydrochloric acid storage tank enters the neutralization kettle, and the pH is adjusted to between 4.7 and 5.

0. After the pH value is stable, the bottom valve of the neutralization kettle is opened, the material in the kettle is finely filtered into the desalting kettle, and the cooling jacket outside the desalting kettle is turned on to cool the temperature to 20-25° C. and temporarily stored; (2) Open the bottom valve of the desalination kettle, and the materials in the kettle enter the nanofiltration membrane for sodium filtration desalination. Samples are taken from the nanofiltration membrane outlet every hour to monitor the conductivity and salinity. When the conductivity drops to 5ms / cm and the salinity drops to less than 3ms / cm, the desalination is terminated; (3) The material after nanofiltration desalination enters the transfer tank, and the cooling jacket on the outside of the transfer tank is turned on to control the temperature to 15-25°C; (4) Open the bottom valve of the transfer tank and the feeding pump, and load the sample at a speed of 500-600L per hour, and load the first anode column and the second anode column in turn. When there is material at the outlet of the second anode column, transfer it to the first cathode column group and the second cathode column group. After the anode column is loaded with sample, wash the column with pure water at 600L per hour until the concentration at the outlet of the anode column is lower than 1g / L. The anode column can be activated and cleaned for use; (5) Open the first eluent valve of the first cathode column group and the second cathode column group, pump pure water and 0.1% formic acid solution into the cathode column at a rate of 500 L per hour, monitor the reaction liquid at the end of the cathode column group during the elution process, and monitor that the material concentration is between 20±5 g / L through the crude citicoline outlet to the fine filtration unit, and then enter the decolorization kettle after fine filtration; (6) Open the chilled water of the condensing jacket outside the decolorization kettle, control the temperature at 15-25° C., open the discharge valve at the bottom of the tank, and allow the reaction liquid to enter the nanofiltration membrane for sodium filtration concentration. The concentrated liquid after nanofiltration concentration is refluxed into the decolorization kettle, and activated carbon is added to the decolorization kettle through a solid feeder. After the activated carbon is decolorized, the citicoline concentrate enters the suction filtration tank for filtration. The filtered activated carbon is discharged through the waste solid outlet, and the filtered citicoline concentrate enters the crystallization kettle; (7) Turn on the feeding pump, the methanol-acetone mixed liquid in the methanol-acetone mixed liquid storage tank enters the crystallization kettle, turn on the steam of the heating jacket outside the crystallization kettle, heat and concentrate the citicoline concentrate, and the distillate after heating and concentration enters the mixed liquid receiving tank after the methanol-acetone is condensed by the condenser, and then flows back to the crystallization kettle, cools down and crystallizes, and enters the centrifuge for centrifugal separation, and the distillate is condensed by the condenser for more than three times and discharged through the sewage outlet at the bottom of the mixed liquid receiving tank; (8) The mother liquor separated by centrifugation is returned to the crystallization kettle for recycling, and the solid separated by centrifugation enters the double cone dryer through the citicoline wet product transfer unit. The dried citicoline finished product enters the finished product packaging and storage process through the citicoline finished product transfer unit.

9. The method for using the citicoline impurity removal and purification device as claimed in claim 8, characterized in that: After three batches of reaction liquid are processed continuously, the first anode column and the second anode column are activated by the bottom-in-top-out / top-in-bottom-out activation method in turn. The activation steps are as follows: (1) Pumping 3% NaOH solution into the first anode column and the second anode column, closing the inlet and outlet valves after loading, and soaking for 4 to 8 hours, wherein the amount of 3% NaOH solution used is 1.5 to 2 times the volume of the resin filled in the anode column; (2) After the alkaline solution washing and soaking is completed, the bottom valve of the anode column is opened, and tap water is pumped into the anode column. The washing is stopped when the pH value at the outlet of the bottom valve of the anode column is 8-9, and the washing liquid is collected and barreled to the sewage treatment station; (3) After the tap water solution washing is completed, open the bottom valve of the anode column and pump 3% hydrochloric acid solution into the anode column. After the loading is completed, close the inlet and outlet valves and soak for more than 4 hours. The amount of 3% hydrochloric acid solution is 1.5 to 2 times the volume of the resin filled in the anode column; (4) After the hydrochloric acid solution washing and soaking is completed, 5 to 6 hours before the column is loaded, open the bottom valve of the anode column and pump pure water into the anode column. Wash until the pH value at the outlet of the bottom valve of the anode column is 5 to 6 and stop. Collect the washing liquid and put it into a barrel and send it to the sewage treatment station.

10. The method for using the citicoline impurity removal and purification device as claimed in claim 8, characterized in that: After three batches of reaction liquid are processed continuously, the first cathode column group and the second cathode column group are activated by the bottom-in-top-out / top-in-bottom-out activation method in turn. The activation steps are as follows: (1) Pump 3% hydrochloric acid solution into the cathode column, close the inlet and outlet valves after loading, and soak for 4 to 8 hours. The amount of 3% hydrochloric acid solution used is 1.5 to 2 times the volume of the resin filled in the cathode column; (2) After the hydrochloric acid solution washing and soaking is completed, the bottom valve of the cathode column is opened, and pure water is pumped into the cathode column. The washing is stopped when the pH value at the outlet of the bottom valve of the cathode column is 5 to 6. The washing liquid is collected and barreled and sent to the sewage treatment station; (3) After washing with pure water solution, open the bottom valve of the cathode column and pump 3% NaOH solution into the cathode column. After loading, close the inlet and outlet valves and soak for more than 4 hours. The amount of 3% NaOH solution is 1.5 to 2 times the volume of the resin filled in the anode column. (4) After the alkaline solution washing and soaking is completed, 5 to 6 hours before the column is loaded, open the cathode column bottom valve and pump pure water into the cathode column. Wash until the pH value at the cathode column bottom valve outlet is 8 to 9 and stop. Collect the washing liquid and put it into a barrel and send it to the sewage treatment station.

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