Method for preparing ferrous succinate through continuous flow

Abstract

The invention belongs to the field of medicinal chemistry, and discloses a method for preparing ferrous succinate by continuous flow, which comprises the following steps: reacting succinic acid and sodium hydroxide in purified water at the temperature of 20-80 DEG C to obtain a reaction phase A; fully and uniformly mixing ferrous sulfate heptahydrate, purified water, concentrated sulfuric acid and iron powder at the temperature of 60-100 DEG C to obtain a reaction phase B; simultaneously pumping the reaction phase A and the reaction phase B into a continuous flow reactor for mixed reaction, and simultaneously pumping alkali liquor to maintain the pH value of the reaction liquid at 5.5-7.5; reaction materials flowing out of the continuous flow reactor enter a tubular heat exchanger and are cooled to 10-70 DEG C for crystallization, and slurry containing ferrous succinate is obtained; the slurry enters a pushing type centrifugal machine for continuous solid-liquid separation, solid washing is conducted with purified water and an organic solvent in sequence while separation is conducted, vacuum drying is conducted, and ferrous succinate is obtained. The ferrous succinate obtained by the method is high in ferrous content and low in high iron content.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry and relates to a method for preparing ferrous succinate, in particular to a method for preparing ferrous succinate by continuous flow. Technical Background

[0002] Ferrous succinate (Formula I) is a second-generation small molecule organic iron, which has the characteristics of good absorption and few side effects. Iron is mainly absorbed in the small intestine, and the absorption of ferrous iron is significantly better than that of ferric iron, but ferrous iron is easily oxidized to ferric iron during storage or molding, which affects the absorption of iron.

[0003]

[0004] There are few synthetic routes for ferrous succinate, mainly the following process routes:

[0005] Method 1 (Literature References: Franke, Ann. 491, 30 (1931) & Chemical Abstracts vol. 79 (1973), p. 320.), the synthetic route is as follows:

[0006]

[0007] The method comprises: using succinic acid and sodium hydroxide as starting materials, first preparing a sodium succinate solution, adding a saturated solution of ferrous sulfate dropwise thereto under the protection of nitrogen, adjusting the pH value to 5.1-5.4 with a saturated sodium bicarbonate solution, heating and refluxing for 40 minutes, cooling, filtering, washing with deionized water, anhydrous ethanol and anhydrous ether, and drying to obtain a product.

[0008] Method 2 (CN101205180A), the synthetic route is as follows:

[0009]

[0010] The method comprises: taking sodium succinate hexahydrate and ferrous sulfate as starting materials and adding a proper amount of antioxidant during the reaction process to obtain the preparation method.

[0011] Method 3 (CN111138271A Example 10), the synthetic route is as follows:

[0012]

[0013] The method comprises: step (1), taking a short-chain organic acid (such as succinic acid) as an acid source and ammonia water as an alkali source, mixing the two in an aqueous solution to prepare organic acid ammonium; step (2), mixing an iron source (ferrous sulfate heptahydrate) with the solution obtained in step (1), stirring, filtering, washing and drying to obtain a high-purity organic metal salt additive to prepare ferrous succinate.

[0014] The inventors analyzed the above process route and found that ferrous succinate is prepared by using succinate or succinic acid as the starting material and then reacting with ferrous sulfate.

[0015] Method 1 is simple to operate and easy to industrialize; however, heating is required during the reaction, and the absence of an antioxidant easily causes the high iron content to increase, resulting in unqualified products. In addition, the use of sodium carbonate to adjust the pH easily introduces ferrous carbonate.

[0016] Method 2 introduces antioxidants to easily control the high iron content; however, the cost of the raw material sodium succinate hexahydrate is relatively high, and the initial pH of the sodium succinate hexahydrate aqueous solution is relatively high, which increases the difficulty of pH control and easily causes crystallization to be too fast, thereby wrapping the raw materials, thereby reducing the conversion rate and increasing the difficulty of post-processing.

[0017] Method three is similar to method one, using ammonia water as the alkali source, but ammonia water is easy to decompose, needs to be prepared, and increases the total volume of the solution. Compared with method one, which uses sodium hydroxide and is more conducive to quantification and control of the reaction liquid volume, method three requires heating during the reaction process, and the absence of antioxidants can easily cause the high iron content to increase, resulting in unqualified products.

[0018] In summary, the existing production of ferrous succinate still remains in the intermittent reactor process stage, resulting in a long reaction time and high cost. In addition, even with nitrogen protection, a small part of ferrous iron will be oxidized to high iron during long-term high-temperature reaction. Therefore, it is necessary to improve the process to prepare a higher purity ferrous succinate product. Summary of the invention

[0019] The invention aims to solve the problem that the ferrous iron content in the existing ferrous succinate production process is prone to be high, especially in the storage process, ferrous iron is oxidized to ferrous iron, which leads to reduced absorption and enhanced bitterness. A method for preparing ferrous succinate by continuous flow is provided. A continuous flow reactor is used to produce high-quality ferrous succinate. Reactants are fully mixed in the continuous flow reactor, and the temperature control is accurate and has a good heat transfer effect. The preset temperature control range is reached quickly, and the amplification effect and the drawback that the reaction heat is difficult to be quickly derived in the traditional kettle reaction in industrial production are eliminated, and the probability of ferrous iron being oxidized to ferrous iron is greatly reduced. The ferrous iron content is extremely high, and the liquid holding volume of the reactor is small, so that intrinsic safety and high-efficiency reaction can be achieved, and the safety problem caused by the difficulty in controlling the reaction temperature in the synthesis process of ferrous succinate is solved.

[0020] The objective of the present invention is achieved through the following technical solutions:

[0021] A method for preparing ferrous succinate by continuous flow, comprising the following steps:

[0022] Step 1: react succinic acid and sodium hydroxide in purified water at a temperature of 20 to 80° C. for 10 min to 1 h, filter to remove mechanical impurities and trace insoluble matter, and obtain reaction phase A;

[0023] Step 2: at a temperature of 60-100° C., ferrous sulfate heptahydrate, purified water, a catalytic amount of concentrated sulfuric acid and iron powder are fully mixed, and mechanical impurities and trace insolubles are removed by filtration to obtain a reaction phase B;

[0024] Step 3: Pumping reaction phase A and reaction phase B into a continuous flow reactor for mixed reaction at the same time, the reaction parameters are: reaction temperature of 50-100° C., residence time of 5-200 seconds; and pumping alkali solution to maintain the pH of the reaction solution at 5.5-7.5;

[0025] Step 4: The reaction material flowing out of the continuous flow reactor enters a tubular heat exchanger, is cooled to 10-70° C. for crystallization, and obtains a slurry containing ferrous succinate; the slurry continuously flows out of the tubular heat exchanger, enters a pusher centrifuge through a material flow pipeline, and the solid and liquid in the slurry are continuously separated in the pusher centrifuge, and the solid is washed with purified water and an organic solvent in sequence during separation, and vacuum dried to obtain ferrous succinate.

[0026] In step 1, the mass volume ratio of succinic acid to purified water is 1:2.0 to 1:10.0 kg / L or g / mL, preferably 1:3.0 to 1:5.5 kg / L or g / mL.

[0027] The molar ratio of succinic acid to sodium hydroxide is 1.0:1.0 to 1.0:4.0, preferably 1.0:1.5 to 1.0:2.5, and more preferably 1.0:1.9 to 1.0:2.1.

[0028] Preferably, the reaction temperature is 40-70° C., and the reaction time is 2 min-1 h.

[0029] More preferably, the reaction temperature is 50-60° C., and the reaction time is 5 min-10 min.

[0030] In step 2, the mass volume ratio of ferrous sulfate heptahydrate to purified water is 1:1.0 to 1:10 kg / L or g / mL, preferably 1:1.5 to 1:5.0 kg / L or g / mL, and more preferably 1:1.5 to 1:3.5 kg / L or g / mL.

[0031] The molar ratio of the ferrous sulfate heptahydrate to sulfuric acid is 1:0.001 to 1:0.05, preferably 1:0.005 to 1:0.015; the molar ratio of the ferrous sulfate heptahydrate to iron powder is 1:0.001 to 1:0.05, preferably 1:0.005 to 1:0.015.

[0032] The mass fraction of the concentrated sulfuric acid is ≥70%. Specifically, the concentrated sulfuric acid is sulfuric acid with a mass fraction of 98%.

[0033] Preferably, ferrous sulfate heptahydrate, purified water, a catalytic amount of concentrated sulfuric acid and iron powder are mixed at a temperature of 80 to 90° C. and stirred to be fully mixed.

[0034] In step 3, preferably, reaction phase A and reaction phase B are pumped into a continuous flow reactor simultaneously by plunger pumps for mixed reaction.

[0035] The molar ratio of succinic acid to ferrous sulfate is 1.0:1.0-1.0:1.4, preferably 1.0:1.05-1.0:1.3; the flow rate of reaction phase A is 10-1000 mL / min, preferably 200-400 mL / min; the flow rate of reaction phase B is 10-1000 mL / min, preferably 300-400 mL / min.

[0036] Preferably, the reaction temperature is 80-90°C.

[0037] Preferably, the residence time is 5 to 200 seconds.

[0038] More preferably, the residence time is 10 to 60 seconds.

[0039] Preferably, an alkali solution is pumped in to maintain the pH of the reaction solution at 6.0-7.0.

[0040] The alkali solution is a sodium hydroxide solution with a mass fraction of 10% to 50%, preferably a sodium hydroxide solution with a mass fraction of 20% to 30%.

[0041] The continuous flow reactor is selected from a dynamic tubular reactor, a microchannel reactor, and a silicon carbide cluster reactor.

[0042] The dynamic tubular reactor has a reaction chamber and a heat exchange chamber. The reaction chamber has a stirring shaft. The stirring mode is: the stirring shaft speed is 60 to 600 rpm, preferably 200 to 400 rpm; or the forward and reverse point oscillation mode is: the oscillation frequency is 3 to 5 Hz.

[0043] In step 4, preferably, the slurry continuously flows out of the tubular heat exchanger, enters the storage tank through the material flow pipeline, and then enters the pusher centrifuge.

[0044] In the pusher centrifuge, the solid and liquid in the slurry are continuously separated. The solid is washed with purified water during centrifugation, filtered and dried, and then washed with an organic solvent, filtered and dried in vacuum to obtain the finished ferrous succinate.

[0045] Preferably, the crystallization temperature is 20 to 60°C. More preferably, the crystallization temperature is 30 to 50°C.

[0046] The end point of the purified water washing is: no turbidity is produced when the filtrate is tested with 20% m / v barium chloride test solution.

[0047] The organic solvent is anhydrous ethanol, 95% ethanol or acetone. The mass volume ratio of succinic acid to the washing organic solvent is 1:2.0 to 1:10 kg / L or g / mL, preferably 1:5.0 to 1:6.0 kg / L or g / mL.

[0048] Compared with the prior art, the present invention has the following beneficial effects:

[0049] The present invention uses a continuous flow process to prepare ferrous succinate, thereby avoiding: (1) potential harm to operators caused by acidic ferrous sulfate solution caused by nitrogen purging at high temperature; and (2) during high-temperature operation, ferrous iron is easily oxidized to ferrous iron because sampling and testing are required and the reaction cannot be closed.

[0050] The present invention suppresses the oxidation of ferrous iron by adding a catalytic amount of concentrated sulfuric acid and iron powder when preparing reaction phase B; using a continuous flow reactor, the raw material has a short residence time in the channel and the reactor has a good heat exchange effect, so that the temperature control in the reaction is accurate and the reaction is rapid, avoiding the difficulty of temperature control in the traditional reactor, the risk of ferrous iron being easily oxidized to ferrous iron due to the long time of dropwise addition, stirring and high temperature reaction, and the method of the present invention can control the ferrous iron content in ferrous succinate to be below 0.1%. In addition, the present invention realizes the preparation of ferrous succinate by continuous flow, and since it is a closed pipeline reaction, there is no need to use nitrogen protection; in particular, it can avoid the situation that when the traditional intermittent reaction materials A and B react, the product is wrapped in raw materials due to the slow reaction of the materials and the crystallization is too fast due to the small solubility, resulting in balling, uneven particle size, low conversion rate, etc.

[0051] In summary, compared with the prior art, the ferrous succinate prepared by the present invention using a continuous flow process has a high ferrous content, an extremely low ferric content, and a more stable quality; continuous production can be achieved; and the method of the present invention is suitable for industrial production. DETAILED DESCRIPTION

[0052] In order to better understand the technical solution of the present invention, the novel method of the present invention is further described below in conjunction with specific embodiments, but this should not be understood as the scope of the subject matter of the present invention being limited to the following examples. All technologies implemented based on the content of the present invention belong to the scope of the present invention.

[0053] The mass fraction of concentrated sulfuric acid used in the examples is 98%.

[0054] The dynamic tubular reactor used in the embodiment has a reaction chamber and a heat exchange chamber. The reaction chamber is provided with a stirring shaft, and a stirring mode or a forward and reverse point oscillation mode can be selected.

[0055] The yield of ferrous succinate was calculated based on the theoretical value of the succinic acid fed.

[0056] Example 1

[0057] Step 1: At a temperature of 50±5°C, succinic acid (11.81 kg, 100.0 mol) and sodium hydroxide (8.0 kg, 200.0 mol) were stirred and dissolved in 40 L of purified water, reacted for 5 min, and mechanical impurities and trace insolubles were removed by filtration to obtain reaction phase A;

[0058] Step 2: At a temperature of 90°C, 60 L of purified water, ferrous sulfate heptahydrate (36.14 kg, 130.0 mol), concentrated sulfuric acid (78.0 g, 0.78 mol), and iron powder (43.6 g, 0.78 mol) were mixed, stirred to mix thoroughly, and mechanical impurities and trace insolubles were removed by filtration to obtain a clear and transparent solution as reaction phase B;

[0059] Step 3, the reaction phase A and the reaction phase B are simultaneously pumped into the reaction chamber of the dynamic tubular reactor by a plunger pump, the flow rate of the reaction phase A is 340 mL / min, the flow rate of the reaction phase B is 363 mL / min, the reaction phase A and the reaction phase B are mixed and reacted in the dynamic tubular reactor, and a 20% mass fraction of sodium hydroxide solution is pumped into the reaction solution. The pH is adjusted to 7.0, and the reaction parameters of the dynamic tubular reactor are controlled as follows: the speed of the stirring shaft is 300 rpm, the reaction temperature is 90 ° C, and the residence time is 16 s;

[0060] Step 4, the reaction material flows out of the dynamic tubular reactor and enters the tubular heat exchanger, the reaction liquid is cooled to 40°C, and a solid product of ferrous succinate is precipitated to obtain a slurry; the slurry continuously flows out of the tubular heat exchanger, enters a storage tank through a material flow pipeline, and then enters a pusher centrifuge, in which the solid and liquid in the slurry are continuously separated, and the solid is washed with purified water while separating until the filtrate is tested with a barium chloride test solution (20%, m / v) without turbidity (the mother liquor after centrifugation is taken), and the filter cake is then washed with anhydrous ethanol (59L) to remove moisture from the product to reduce the drying time, and vacuum dried to obtain yellow ferrous succinate (16.85kg, 35.53% ferrous iron, 0.08% ferrous iron, and a yield of 98.02%).

[0061] Example 2

[0062] Step 1: At a temperature of 50±5°C, succinic acid (11.81 kg, 100.0 mol) and sodium hydroxide (8.0 kg, 200.0 mol) were stirred and dissolved in 60 L of purified water, reacted for 10 min, and mechanical impurities and trace insolubles were removed by filtration to obtain reaction phase A;

[0063] Step 2: At a temperature of 85°C, 90 L of purified water, ferrous sulfate heptahydrate (33.36 kg, 120.0 mol), concentrated sulfuric acid (97.0 g, 0.97 mol), and iron powder (54.2 g, 0.97 mol) were mixed, stirred to mix thoroughly, and mechanical impurities and trace insolubles were removed by filtration to obtain a clear and transparent solution as reaction phase B;

[0064] Step 3, the reaction phase A and the reaction phase B are simultaneously pumped into the reaction chamber of the dynamic tubular reactor with a plunger pump, the flow rate of the reaction phase A is 231.5 mL / min, the flow rate of the reaction phase B is 344 mL / min, the reaction phase A and the reaction phase B are mixed and reacted in the dynamic tubular reactor, and a 25% mass fraction of sodium hydroxide solution is pumped into the reaction solution. The pH is adjusted to 6.8, and the reaction parameters of the dynamic tubular reactor are controlled as follows: the speed of the stirring shaft is 150 rpm, the reaction temperature is 85 ° C, and the residence time is 20s;

[0065] Step 4, the reaction material flows out of the dynamic tubular reactor and enters the tubular heat exchanger, the reaction liquid is cooled to 50°C, and a solid product of ferrous succinate is precipitated to obtain a slurry; the slurry is continuously discharged from the tubular heat exchanger, enters a storage tank through a material flow pipeline, and then enters a pusher centrifuge, in which the solid and liquid in the slurry are continuously separated, and the solid is washed with purified water while separating until the filtrate is tested with a barium chloride test solution (20%, m / v) and no turbidity is generated; the filter cake is then washed with 95% ethanol (70.8L) and vacuum dried to obtain yellow ferrous succinate (16.98kg, ferrous iron 35.62%, ferrous iron 0.06%, and a yield of 98.78%).

[0066] Example 3

[0067] Step 1: At a temperature of 50±5°C, succinic acid (11.81 kg, 100.0 mol) and sodium hydroxide (8.0 kg, 200.0 mol) were stirred and dissolved in 50 L of purified water, reacted for 8 min, and mechanical impurities and trace insolubles were removed by filtration to obtain reaction phase A;

[0068] Step 2: At a temperature of 80°C, 100 L of purified water, ferrous sulfate heptahydrate (29.20 kg, 105.0 mol), concentrated sulfuric acid (81.0 g, 0.81 mol), and iron powder (45.2 g, 0.81 mol) were mixed, stirred to mix thoroughly, and mechanical impurities and trace insolubles were removed by filtration to obtain a clear and transparent solution as reaction phase B;

[0069] Step 3, the reaction phase A and the reaction phase B are simultaneously pumped into the reaction chamber of the dynamic tubular reactor by a plunger pump, the flow rate of the reaction phase A is 236.5 mL / min, the flow rate of the reaction phase B is 373 mL / min, the reaction phase A and the reaction phase B are mixed and reacted in the dynamic tubular reactor, and a 30% mass fraction of sodium hydroxide solution is pumped into the reaction solution to adjust the pH to 6.5, and the reaction parameters of the dynamic tubular reactor are controlled as follows: forward and reverse point oscillation mode, frequency of 4 Hz, reaction temperature of 80 ° C, residence time of 19 s;

[0070] Step 4, the reaction material flows out of the dynamic tubular reactor and enters the tubular heat exchanger, the reaction liquid is cooled to 60°C, and a solid product of ferrous succinate is precipitated to obtain a slurry; the slurry is continuously discharged from the tubular heat exchanger, enters a storage tank through a material flow pipeline, and then enters a pusher centrifuge, in which the solid and liquid in the slurry are continuously separated, and the filtrate is washed with purified water while separating until the filtrate is tested with a barium chloride test solution (20%, m / v) without turbidity, and the filter cake is then washed with acetone (65L) and vacuum dried to obtain yellow ferrous succinate (16.90kg, 35.58% ferrous iron, 0.05% ferrous iron, and a yield of 98.31%).

Claims

1. A method for preparing ferrous succinate by continuous flow, characterized in that: The following steps are involved: Step 1: react succinic acid and sodium hydroxide in purified water at a temperature of 20 to 80° C. for 10 min to 1 h, and filter to obtain reaction phase A; Step 2: at a temperature of 60-100° C., ferrous sulfate heptahydrate, purified water, a catalytic amount of concentrated sulfuric acid and iron powder are fully mixed and filtered to obtain a reaction phase B; Step 3: Pumping reaction phase A and reaction phase B into a continuous flow reactor for mixed reaction at the same time, the reaction parameters are: reaction temperature of 50-100° C., residence time of 5-200 seconds; and pumping alkali solution to maintain the pH of the reaction solution at 5.5-7.5; Step 4: The reaction material flowing out of the continuous flow reactor enters a tubular heat exchanger, is cooled to 10-70° C. for crystallization, and obtains a slurry containing ferrous succinate; the slurry continuously flows out of the tubular heat exchanger, enters a pusher centrifuge through a material flow pipeline, and the solid and liquid in the slurry are continuously separated in the pusher centrifuge, and the solid is washed with purified water and an organic solvent in sequence during separation, and vacuum dried to obtain ferrous succinate.

2. The method for preparing ferrous succinate by continuous flow according to claim 1, characterized in that: In step 1, the mass volume ratio of the succinic acid to purified water is 1:2.0 to 1:10.0 kg / L or g / mL, preferably 1:3.0 to 1:5.5 kg / L or g / mL; the molar ratio of the succinic acid to sodium hydroxide is 1.0:1.0 to 1.0:4.0, preferably 1.0:1.5 to 1.0:2.5, and more preferably 1.0:1.9 to 1.0:2.

1.

3. The method for preparing ferrous succinate by continuous flow according to claim 1, characterized in that: In step 1, the reaction temperature is 40-70° C., and the reaction time is 2 min to 1 h; preferably, the reaction temperature is 50-60° C., and the reaction time is 5 min to 10 min.

4. The method for preparing ferrous succinate by continuous flow according to claim 1, characterized in that: In step 2, the mass volume ratio of the ferrous sulfate heptahydrate to purified water is 1:1.0 to 1:10 kg / g / mL, preferably 1:1.5 to 1:5.0 kg / L or g / mL, and more preferably 1:1.5 to 1:3.5 kg / L or g / mL; the molar ratio of the ferrous sulfate heptahydrate to sulfuric acid is 1:0.001 to 1:0.05, preferably 1:0.005 to 1:0.015; the molar ratio of the ferrous sulfate heptahydrate to iron powder is 1:0.001 to 1:0.05, preferably 1:0.005 to 1:0.

015.

5. The method for preparing ferrous succinate by continuous flow according to claim 1, characterized in that: In step 2, ferrous sulfate heptahydrate, purified water, a catalytic amount of concentrated sulfuric acid and iron powder are mixed at a temperature of 80-90° C. and stirred to be fully mixed.

6. The method for preparing ferrous succinate by continuous flow according to claim 1, characterized in that: In step 3, the molar ratio of succinic acid to ferrous sulfate is 1.0:1.0-1.0:1.4, preferably 1.0:1.05-1.0:1.3; the flow rate of reaction phase A is 10-1000 mL / min, and the flow rate of reaction phase B is 10-1000 mL / min.

7. The method for preparing ferrous succinate by continuous flow according to claim 1, characterized in that: In step 3, the reaction temperature is 80-90° C.; the residence time is 5-200 seconds, preferably 10-60 seconds.

8. The method for preparing ferrous succinate by continuous flow according to claim 1, characterized in that: In step three, an alkali solution is pumped in to maintain the pH of the reaction solution at 6.0-7.0; the alkali solution is a sodium hydroxide solution with a mass fraction of 10%-50%, preferably a sodium hydroxide solution with a mass fraction of 20%-30%.

9. The method for preparing ferrous succinate by continuous flow according to claim 1, characterized in that: In step three, the continuous flow reactor is selected from a dynamic tubular reactor, a microchannel reactor, and a silicon carbide cluster reactor; the dynamic tubular reactor has a reaction chamber and a heat exchange chamber, and the reaction chamber has a stirring shaft, and the stirring mode is: the stirring shaft speed is 60 to 600 rpm, preferably 200 to 400 rpm; or the forward and reverse point oscillation mode: 3 to 5 Hz.

10. The method for preparing ferrous succinate by continuous flow according to claim 1, characterized in that: In step 4, the crystallization temperature is 20 to 60° C., preferably 30 to 50° C.; The end point of the purified water washing is: no turbidity is produced when the filtrate is tested with 20% m / v barium chloride test solution. The organic solvent is anhydrous ethanol, 95% ethanol or acetone; the mass volume ratio of succinic acid to the washing organic solvent is 1:2.0 to 1:10 kg / L or g / mL, preferably 1:5.0 to 1:6.0 kg / L or g / mL.

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