Synthesis method of iron maltol crystal form II

Abstract

The invention relates to a synthesis method of an iron maltol crystal form II, which can directly obtain the iron maltol crystal form II through a process of firstly adding a crystal form II seed crystal into water and then adding an alkaline solution of maltol and an aqueous solution of ferric salt, thereby avoiding a crystal transformation process, obviously shortening the stirring time of a subsequent reaction solution and reducing the time required by a preparation process. The crystal form preparation period is shortened; meanwhile, the iron maltol prepared by the method is high in purity and does not contain a crystal form I, so that the risk of crystal mixing is reduced; no matter in a small-batch gram level or a large-batch kilogram level, the high-purity and high-yield iron maltol crystal form II can be obtained by using the process. Furthermore, according to the method, water is used for replacing an organic solvent, the technological operation is simple and efficient, the high-purity and high-yield iron maltol crystal form II can be prepared, and the method is suitable for industrial production amplification.

Description

Technical Field

[0001] The present application relates to the technical field of drug synthesis, and in particular to a method for synthesizing maltol iron crystal form II. Background Art

[0002] Ferric Maltol, also known as Ferric Maltol in English, has a chemical name of 3-hydroxy-2-methyl-4H-pyran-4-one iron (III) complex (3:1). Ferric Maltol was approved in the European Union in February 2016 and in the United States in July 2019. It can be used to treat iron deficiency in adults. Its structural formula is as follows:

[0003] .

[0004] There are five main methods for preparing maltol iron reported in the literature:

[0005] Patent document (CN103443091B) reports a method for preparing maltol iron as shown in Formula 1. This route produces two by-products that consume a large amount of maltol, namely Fe(OH)2(maltol) and Fe(OH)(maltol)2, which is not suitable for industrial scale-up production.

[0006] (Formula 1)

[0007] Patent document (CN109071481A) reports a method for preparing maltol iron as shown in Formula 2. This route has a slow reaction and requires a long period of oxygen blowing. In addition, unreacted iron filings are mixed with the product and are difficult to separate, making it unsuitable for industrial scale-up production.

[0008] (Formula 2)

[0009] Patent document (CN109311837A) reports a method for preparing maltol iron as shown in Formula 3. This route requires controlling the rate of gel formation to prevent the formation of lumps at the bottom of the reaction tank, and is not suitable for industrial scale-up production.

[0010] (Formula 3)

[0011] Patent document (CN109790138A) reports a method for preparing maltol iron as shown in Formula 4. This route requires controlling the rate of gel formation to prevent the formation of lumps at the bottom of the reaction tank, and is not suitable for industrial scale-up production.

[0012] (Formula 4)

[0013] At the same time, the study found that there are multiple crystal forms in maltol iron, among which crystal form II has higher stability after being placed for a longer time compared with other crystal forms, and is also the main form of existence. A patent document discloses a method for preparing crystal form II, which includes adding ferric citrate solution to sodium maltol solution. In the case of type II inoculation, stirring at 25°C overnight can obtain a mixture of crystal form I and crystal form II, and heating to 40°C and stirring overnight can separate crystal form II. The method for preparing maltol iron crystal form II has the following defects: in order to make maltol react completely, it is easy to cause excessive ferric citrate and increase the risk of raw material residue; in the process of adding ferric citrate to sodium maltol, the ratio of the two is less than 1:3, and the concentration ratio of iron ions and maltol ions in the reaction system is uncertain, which is not conducive to the generation of maltol iron and may introduce hydroxide impurities; during crystallization, crystal form I is first produced and then crystallized to form crystal form II, and the slurry stirring time of the precipitate is as long as 36-48 hours, which makes the purity and yield of crystal form II low, increases production cost and management cost, and is not suitable for industrial scale-up production. In addition, there are also patent documents reporting a method for preparing maltol iron crystal form II, including dropping ferric citrate solution into a methanol aqueous solution of maltol, and then dropping a methanol solution of sodium methoxide, and stirring at 50°C-60°C for 24 hours to separate the maltol iron crystal form II product. The method uses methanol solvent, introduces organic solvent impurities, has a long stirring time, increases production cost and management cost, and is not suitable for industrial scale-up production. Summary of the invention

[0014] Based on this, it is necessary to provide a method for synthesizing maltol iron crystal form II, which uses water instead of organic solvent, has simple and efficient process operation, can prepare high-purity and high-yield maltol iron crystal form II, and is suitable for industrial production and amplification.

[0015] The technical solution of this application is as follows:

[0016] The present invention provides a method for synthesizing maltol iron crystal form II, comprising the following steps:

[0017] mixing maltol and an alkaline aqueous solution to prepare an alkaline solution of maltol;

[0018] Mixing iron salt and water to prepare an iron salt aqueous solution;

[0019] Adding seeds of maltol iron crystal form II into water, then adding the alkaline solution of maltol and the iron salt aqueous solution, stirring, filtering and drying, to prepare maltol iron crystal form II.

[0020] In one embodiment, the alkaline solution of maltol and the aqueous solution of iron salt are added in a manner of adding the alkaline solution of maltol and the aqueous solution of iron salt into the reaction system at the same time.

[0021] In one embodiment, the alkaline solution of maltol and the aqueous solution of iron salt are added dropwise.

[0022] In one embodiment, the stirring step satisfies at least one of the following conditions:

[0023] (1) Duration: 2h-8h;

[0024] (2) The temperature is 20℃-30℃.

[0025] In one embodiment, the drying step satisfies at least one of the following conditions:

[0026] (1) Temperature is 50℃-80℃;

[0027] (2) The time is 16h-36h.

[0028] In one embodiment, the alkaline aqueous solution is one or both of a sodium hydroxide aqueous solution and a potassium hydroxide aqueous solution.

[0029] In one embodiment, the mass percentage of alkali in the alkaline aqueous solution is 15%-30%.

[0030] In one embodiment, the iron salt is one or more of ferric citrate pentahydrate, ferric chloride or anhydrous ferric citrate.

[0031] In one of the embodiments, in the iron salt aqueous solution, the mass ratio of iron salt to water is 1:(3-5).

[0032] In one embodiment, the mass ratio of the maltol iron form II seed crystal to maltol is 1:(5-115).

[0033] Compared with the prior art, this application has the following beneficial effects:

[0034] Different from the preparation method of the prior art of first mixing maltol and ferric citrate and then adding crystal seeds, the present application first adds crystal form II seeds in water, and then adds an alkaline solution of maltol and an iron salt aqueous solution, which can directly obtain maltol iron crystal form II, avoid the process of crystal transformation, significantly shorten the stirring time of the subsequent reaction solution, reduce the time required for the preparation process, and shorten the crystal preparation cycle; at the same time, the maltol iron prepared by the method has high purity, does not contain crystal form I, and reduces the risk of mixed crystals; whether it is a small batch of grams or a large batch of kilograms, the process can be used to obtain high-purity and high-yield maltol iron crystal form II. Further, the method replaces organic solvents with water, and the process operation is simple and efficient, and high-purity and high-yield maltol iron crystal form II can be prepared, which is suitable for industrial production and amplification. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0036] FIG1 is an X-ray powder diffraction pattern of maltol iron crystal form II obtained in Example 1.

[0037] FIG2 is an X-ray powder diffraction pattern of maltol iron crystal form II obtained in Comparative Example 1. DETAILED DESCRIPTION

[0038] The following is a further detailed description of a method for synthesizing ferric maltol crystal form II of the present application in conjunction with specific examples. The present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present application more thorough and comprehensive.

[0039] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0040] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0041] As used herein, "one or more" refers to any one, any two, or any two or more of the listed items.

[0042] Herein, the optional scope of "and / or", "or / and", and "and / or" includes any one of two or more relevant listed items, and also includes any and all combinations of the relevant listed items, wherein said any and all combinations include any two relevant listed items, any more relevant listed items, or a combination of all relevant listed items. (It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in the present application, the technical solution undoubtedly includes technical solutions that are all connected by "logical AND", and also undoubtedly includes technical solutions that are all connected by "logical OR". For example, "A and / or B" includes three parallel solutions of A, B and A+B. For another example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, technical solutions that are all connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, a combination of any two or any three of A, B, C, and D, and also includes a combination of four items of A, B, C, and D (that is, a technical solution that is all connected by "logical AND").)

[0043] Herein, "further", "further", "particularly" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0044] Herein, "first aspect", "second aspect", "third aspect", "fourth aspect", etc. are used for descriptive purposes only and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. In addition, "first", "second", "third", "fourth", etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In the description of the present application, the meaning of "multiple" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined. In the description of the present application, the meaning of "several" is at least one, such as one, two, etc., unless otherwise clearly and specifically defined.

[0045] In this application, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0046] Specifically, only some numerical ranges are specifically disclosed herein. However, any lower limit can be combined with any upper limit to form an undefined range; and any lower limit can be combined with other lower limits to form an undefined range, and any upper limit can be combined with any other upper limit to form an undefined range. In addition, each individually disclosed point or single value itself can be combined with any other point or single value as a lower limit or upper limit or with other lower limits or upper limits to form an undefined range. The use of numerical ranges represented by endpoints includes all numbers within the range and any range within the range, for example, 1 to 5 includes 1, 1.1, 1.3, 1.5, 2, 2.75, 3, 3.80, 4 and 5, etc.

[0047] The percentage contents involved in this application, unless otherwise specified, refer to mass percentage for solid-liquid mixing and solid-solid mixing, and refer to volume percentage for liquid-liquid mixing.

[0048] The percentage concentrations mentioned in this application, unless otherwise specified, refer to the final concentration, which refers to the percentage of the added component in the system after the addition of the component.

[0049] The temperature parameters in this application, unless otherwise specified, allow both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within the range of ±5°C, ±2°C, ±1°C, ±0.5°C, ±0.4°C, ±0.3°C, ±0.2°C, and ±0.1°C are allowed. Normal temperature or room temperature in this application refers to no temperature control operation, generally 4°C~35°C, preferably 20±5°C.

[0050] The present invention provides a method for synthesizing maltol iron crystal form II, comprising the following steps:

[0051] mixing maltol and an alkaline aqueous solution to prepare an alkaline solution of maltol;

[0052] Mixing iron salt and water to prepare an iron salt aqueous solution;

[0053] Adding seeds of maltol iron crystal form II into water, then adding the alkaline solution of maltol and the iron salt aqueous solution, stirring, filtering and drying, to prepare maltol iron crystal form II.

[0054] In one specific example, the alkaline solution of maltol and the aqueous solution of iron salt are added in a manner of adding the alkaline solution of maltol and the aqueous solution of iron salt into the reaction system at the same time.

[0055] In some of the examples, the alkaline solution of maltol and the aqueous solution of iron salt are added dropwise.

[0056] In some of these examples, the stirring step includes a condition of 2h-8h. It is understandable that the stirring time includes but is not limited to 2h, 3h, 4h, 5h, 6h, 7h, 8h. Further, the stirring time is 2h-6h. Further, the stirring time is 2h-3h.

[0057] In some examples, the stirring step comprises a temperature of 20° C. to 30° C. It is understood that the stirring temperature includes, but is not limited to, 20° C., 22° C., 24° C., 26° C., 28° C., and 30° C.

[0058] In some examples, the conditions of the drying step include: a temperature of 50° C.-80° C. It can be understood that the drying temperature includes but is not limited to 50° C., 55° C., 60° C., 65° C., 70° C., 75° C., and 80° C.

[0059] In some examples, the conditions of the drying step include: a time of 16 hours to 36 hours. It can be understood that the drying time includes but is not limited to 16 hours, 20 hours, 24 hours, 28 hours, 32 hours, and 36 hours.

[0060] In some examples, the alkaline aqueous solution is one or both of a sodium hydroxide aqueous solution and a potassium hydroxide aqueous solution.

[0061] In some examples, the mass percentage of alkali in the alkaline aqueous solution is 15%-30%. It is understandable that the mass percentage of alkali in the alkaline aqueous solution includes but is not limited to 15%, 20%, 25%, and 30%.

[0062] In some examples, the iron salt is one or more of ferric citrate pentahydrate, ferric chloride, or anhydrous ferric citrate.

[0063] In some examples, the mass ratio of iron salt to water in the iron salt aqueous solution is 1:(3-5). It can be understood that the mass ratio of iron salt to water includes but is not limited to 1:3, 1:3.5, 1:4, 1:4.5, 1:5.

[0064] In some examples, the molar ratio of maltol to iron salt is (2-5): 1. Furthermore, the molar ratio of maltol to iron salt is 3:1.

[0065] In some of the examples, in the step of mixing maltol and the alkaline aqueous solution, the mixing time is 0.5 h-1 h.

[0066] In some of the examples, in the step of mixing the iron salt and the water, the mixing time is 2 h to 4 h.

[0067] In some examples, the mass ratio of the seed crystals of the ferric maltol crystal form II to maltol is 1:(5-115). Further, the mass ratio of the seed crystals of the ferric maltol crystal form II to maltol is 1:(5-15). It is understandable that the mass ratio of the seed crystals of the ferric maltol crystal form II to maltol includes but is not limited to 1:5, 1:7, 1:10, 1:12, 1:15.

[0068] In some examples, the mass ratio of the seed crystal of ferric maltol crystal form II to ferric citrate pentahydrate is 1:(5-100). It can be understood that the mass ratio of the seed crystal of ferric maltol crystal form II to ferric citrate pentahydrate includes but is not limited to 1:5, 1:10, and 1:100.

[0069] In some examples, in the step of adding the alkaline solution of maltol and the aqueous solution of iron salt, the temperature of the reaction system is less than or equal to 30°C.

[0070] In one specific example, the synthesis method of the maltol iron crystal form II comprises the following steps:

[0071] mixing maltol and an alkaline aqueous solution to prepare an alkaline solution of maltol;

[0072] Mixing ferric citrate pentahydrate and water to prepare a ferric citrate aqueous solution;

[0073] The seeds of ferric maltol crystal form II are added into water, and then the alkaline solution of maltol and the aqueous solution of ferric citrate are added dropwise while stirring, and the mixture is stirred, filtered and dried to prepare ferric maltol crystal form II.

[0074] In some of the examples, the ferric citrate aqueous solution is prepared by adding iron salt to purified water, heating and stirring to dissolve, and then cooling to room temperature before use.

[0075] In some of the examples, the alkaline solution of maltol is prepared by adding maltol to an aqueous sodium hydroxide solution and stirring to dissolve the maltol before use.

[0076] The synthesis process of ferric maltol provided by the present invention comprises 1 step, which is specifically as follows:

[0077]

[0078] Different from the preparation method of the prior art which first mixes maltol and ferric citrate and then adds crystal seeds, the present invention can directly obtain ferric maltol crystal form II by first adding crystal seeds of form II into water and then simultaneously adding a sodium hydroxide solution of maltol and an aqueous solution of ferric citrate dropwise, thereby avoiding the process of crystal transformation and significantly shortening the stirring time of the subsequent reaction solution to only 2-8 hours, thereby reducing the time required for the preparation process and shortening the crystal preparation cycle; the ferric maltol prepared by the method has high purity, does not contain form I, and reduces the risk of mixed crystals; whether it is a small batch of grams or a large batch of kilograms, the process of the present invention can obtain ferric maltol crystal form II with high purity and high yield.

[0079] In some examples, the powder X-ray diffraction pattern of the ferric maltol crystal form II is substantially as shown in Figure 1. The X-ray powder diffraction pattern of the ferric maltol crystal form II has characteristic diffraction peaks at the following 2θ (°) angles: about (i.e., approximately or roughly) 8.3 degrees, 11.8 degrees, 13.4 degrees, 14.5 degrees, and 15.6 degrees each, and optionally one or more, two or more, three or more, or each ±0.25 degrees, or ±0.2 degrees, or ±0.1 degrees, such as a characteristic crystal peak of about ±0.05 degrees of 2θ value (in degrees).

[0080] The following is further described in conjunction with specific embodiments. The raw materials involved in the following specific embodiments, unless otherwise specified, can all be commercially available; the instruments used, unless otherwise specified, can all be commercially available; the processes involved, unless otherwise specified, are all routinely selected by those skilled in the art, and may preferably refer to the guidance given in the present application document, and may also refer to the experimental manual in the field or other experimental methods known in the field, or refer to the experimental conditions recommended by the manufacturer.

[0081] The following are specific embodiments.

[0082] The Fe(III) content was determined by potentiometric titration (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0701);

[0083] The method for determining the maltol content is: high performance liquid chromatography (General Rules 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0084] Example 1

[0085] This example conducts a small batch experiment on the synthesis of maltol iron crystal form II, as follows:

[0086] Mix maltol (564.7g, 3eq) and 15% sodium hydroxide aqueous solution (1194g), stir for 1h, cool to 30℃ and filter for later use. Heat ferric citrate pentahydrate (500g, 1eq) and purified water (2000g) to 100℃ and stir for 2h. After stirring, cool to 30℃, filter and set aside. Add purified water (400g) and seed crystals (50g of crystal form II) to the reaction bottle. While stirring, drip ferric citrate aqueous solution and maltol aqueous solution into the aqueous solution at the same time, and control the temperature not to exceed 30℃. After the addition is completed, stir at 30℃ for 2h. Filter, wash the filter cake with purified water (500g), and dry to obtain a wet product, which is vacuum dried at 60℃ for 20h. The yield is 97.6%, the purity is 100%, the Fe(III) content is 13.2%, the maltol content is 88.4%, and the X-ray powder diffraction (XRD) result is shown in FIG1 . The XRD result is Form II.

[0087] Example 2

[0088] This example conducts a large-scale experiment on the synthesis of maltol iron crystal form II, as follows:

[0089] Add water (27.6kg) to dilute 30% alkali solution (27.6kg) to 15% (w / w) sodium hydroxide aqueous solution, then add maltol (45.2kg, 3eq), stir to dissolve, and set aside at 40℃. Heat ferric citrate pentahydrate (40kg, 1eq) and purified water (160kg) to 100℃, stir for 2h, and cool to 30℃ after stirring. Add purified water (100kg) and seed crystals (form II, 4kg) to the reactor, and filter the ferric citrate aqueous solution and maltol aqueous solution in batches and add them to the aqueous solution under stirring, and control the temperature not to exceed 30℃. After the addition is completed, stir at 20℃ for 2h. Centrifuge and wash the filter cake with purified water (40kg) to obtain a wet product, which is vacuum dried at 60℃ for 20h. The yield was 95.8%, the purity was 100%, the Fe(III) content was 13.3%, the maltol content was 88.0%, and the XRD result was Form II.

[0090] Example 3

[0091] Mix maltol (113g, 3eq) and 15% sodium hydroxide aqueous solution (238.7g), stir for 1h, cool to 30℃ and filter for later use. Heat ferric citrate pentahydrate (100g, 1eq) and purified water (400g) to 100℃ and stir for 2h. After stirring, cool to 30℃ and filter for later use. Add purified water (80g) and seed crystals (form II, 10g) to the reaction bottle. Under stirring, drip ferric citrate aqueous solution and maltol aqueous solution into the aqueous solution at the same time, and control the temperature not to exceed 30℃. After the addition is completed, stir at 20-30℃ for 2h. Filter, wash the filter cake with purified water (100g), drain to obtain the wet product, and vacuum dry at 60℃ for 20h. Yield 93.28%, purity 100%.

[0092] Example 4

[0093] Mix maltol (113g, 3eq) and 15% sodium hydroxide aqueous solution (238.7g), stir for 1h, cool to 30℃ and filter for later use. Heat ferric citrate pentahydrate (100g, 1eq) and purified water (400g) to 100℃ and stir for 2h. Cool to 30℃ after stirring, filter and set aside. Add purified water (80g) and seed crystals (form II, 10g) to the reaction bottle. Under stirring, drip ferric citrate aqueous solution and maltol aqueous solution into the aqueous solution at the same time, and control the temperature not to exceed 30℃. After the addition is completed, stir at 20-30℃ for 4h. Filter, wash the filter cake with purified water (100g), drain to obtain the wet product, and vacuum dry at 60℃ for 20h. Yield 95.41%, purity 100%.

[0094] Example 5

[0095] Mix maltol (113g, 3eq) and 15% sodium hydroxide aqueous solution (238.7g), stir for 1h, cool to 30℃ and filter for later use. Heat ferric citrate pentahydrate (100g, 1eq) and purified water (400g) to 100℃ and stir for 2h. Cool to 30℃ after stirring, filter and set aside. Add purified water (80g) and seed crystals (form II, 10g) to the reaction bottle. Under stirring, drip ferric citrate aqueous solution and maltol aqueous solution into the aqueous solution at the same time, and control the temperature not to exceed 30℃. After the addition is completed, stir at 20-30℃ for 8h. Filter, wash the filter cake with purified water (100g), drain to obtain the wet product, and vacuum dry at 60℃ for 20h. Yield 95.23%, purity 100%.

[0096] Example 6

[0097] Mix maltol (113g, 3eq) and 15% sodium hydroxide aqueous solution (238.7g), stir for 1h, cool to 30℃ and filter for later use. Heat ferric citrate pentahydrate (100g, 1eq) and purified water (400g) to 100℃ and stir for 2h. After stirring, cool to 30℃ and filter for later use. Add purified water (80g) and seed crystals (crystal form II, 1g) to the reaction bottle. Under stirring, drip ferric citrate aqueous solution and maltol aqueous solution into the aqueous solution at the same time, and control the temperature not to exceed 30℃. After the addition is completed, stir at 20-30℃ for 8h. Filter, wash the filter cake with purified water (100g), drain to obtain the wet product, and vacuum dry at 60℃ for 20h. Yield 92.32%, purity 100%.

[0098] Example 7

[0099] Mix maltol (113g, 3eq) and 15% sodium hydroxide aqueous solution (238.7g), stir for 1h, cool to 30℃ and filter for later use. Heat ferric citrate pentahydrate (100g, 1eq) and purified water (400g) to 100℃ and stir for 2h. Cool to 30℃ after stirring, filter and set aside. Add purified water (80g) and seed crystals (crystal form II, 20g) to the reaction bottle. Under stirring, drip ferric citrate aqueous solution and maltol aqueous solution into the aqueous solution at the same time, and control the temperature not to exceed 30℃. After the addition is completed, stir at 20-30℃ for 8h. Filter, wash the filter cake with purified water (100g), drain to obtain the wet product, and vacuum dry at 60℃ for 20h. Yield 99.46%, purity 100%.

[0100] Comparative Example 1

[0101] This comparative example 1 carries out the reproduction test of the original research patent (CN107001310B), and the details are as follows

[0102] Add maltol (6.39g, 2.5eq) to 6M sodium hydroxide (9mL), stir to dissolve, filter, and set aside the filtrate. Add ferric citrate (5g, 1eq) to water (20mL), heat to 90℃-100℃, filter after dissolving, and cool the filtrate for use. Under room temperature and stirring conditions, add ferric citrate solution to sodium maltol solution, then add maltol iron type II (50mg), heat to 40℃, stir overnight, filter, wash the filter cake with purified water (5g), and obtain a wet product. The wet product is vacuum dried at 60℃ for 16h-24h. The yield is 71.2%, the purity is 99.92%, and the XRD results are shown in Figure 2, which is crystal form II.

[0103] Investigation Example 1

[0104] This investigation example conducted an exploratory test with and without seed crystals, as follows:

[0105] As shown in Table 1, maltol (564.7g) and 15% sodium hydroxide aqueous solution (1194g) were mixed, stirred for 0.5h-1h, cooled to 20℃-30℃ and filtered for use. Ferric citrate (500g) and purified water (2000g) were heated to 90℃-100℃ and stirred for 2h-4h. After stirring, the mixture was cooled to 20-30℃ and filtered for use. Purified water (400g) and seed crystals (50g of crystal form II) / without seed crystals were added to the reaction bottle. Under stirring, the ferric citrate aqueous solution and the maltol aqueous solution were simultaneously dripped into the aqueous solution, and the temperature was controlled not to exceed 30℃. After the addition was completed, the mixture was stirred at 20-30℃ for 2h-3h. Filter, wash the filter cake with purified water (500g), and drain to obtain a wet product. The wet product was retained and vacuum dried at 60℃ for 16h-24h.

[0106] Table 1

[0107]

[0108] Conclusion: Compared with the stirring time required for mixing ferric citrate and sodium maltol first and then adding ferric maltol type II seeds in comparative example 1, the present investigation example first adds ferric maltol type II seeds and only needs stirring for 2-3 hours to obtain ferric maltol that is entirely type II. Therefore, adding ferric maltol type II seeds first can effectively reduce the stirring time.

[0109] Investigation Example 2

[0110] This investigation example conducted an experiment on the addition method, as shown in Table 2 below:

[0111] Table 2

[0112]

[0113] Conclusion: When no seed crystal is added, after sequential mixing or simultaneous mixing of the maltol solution and the ferric citrate solution, after 2-3 hours of stirring, both tend to obtain Form I, but sequential mixing is prone to produce a mixture of two forms, while simultaneous mixing can ensure the purity of the form. In addition, by mixing the maltol solution and the ferric citrate solution simultaneously, the excess raw material residue and impurities in the product are reduced.

[0114] Combined with the difference in crystal purity between simultaneous mixing and sequential mixing in Investigation Example 2, under the condition of adding seed crystals first, mixed crystals may be produced regardless of whether the ferric citrate solution or the maltol aqueous solution is added first; on the contrary, a complete crystal form II can be obtained by adding the ferric citrate solution and the maltol aqueous solution at the same time.

[0115] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0116] The above-described embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be construed as limiting the scope of the patent application. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent application shall be subject to the attached claims, and the description may be used to interpret the content of the claims.

Claims

1. A method for synthesizing maltol iron crystal form II, characterized in that: The following steps are involved: mixing maltol and an alkaline aqueous solution to prepare an alkaline solution of maltol; Mixing iron salt and water to prepare an iron salt aqueous solution; Adding seeds of maltol iron crystal form II into water, then adding the alkaline solution of maltol and the iron salt aqueous solution, stirring, filtering and drying, to prepare maltol iron crystal form II.

2. The method for synthesizing maltol iron crystal form II according to claim 1, characterized in that: The alkaline solution of maltol and the aqueous solution of iron salt are added in a manner of adding the alkaline solution of maltol and the aqueous solution of iron salt into the reaction system at the same time.

3. The method for synthesizing maltol iron crystal form II according to claim 1, characterized in that: The alkaline solution of maltol and the aqueous solution of iron salt are added dropwise.

4. The method for synthesizing maltol iron crystal form II according to claim 1, characterized in that: The stirring step satisfies at least one of the following conditions: (1) Duration: 2h-8h; (2) The temperature is 20℃-30℃.

5. The method for synthesizing maltol iron crystal form II according to claim 1, characterized in that: The drying step satisfies at least one of the following conditions: (1) Temperature is 50℃-80℃; (2) The time is 16h-36h.

6. The method for synthesizing maltol iron crystal form II according to claim 1, characterized in that: The alkaline aqueous solution is one or both of a sodium hydroxide aqueous solution and a potassium hydroxide aqueous solution.

7. The method for synthesizing maltol iron crystal form II according to claim 6, characterized in that: In the alkaline aqueous solution, the mass percentage of alkali is 15%-30%.

8. The method for synthesizing maltol iron crystal form II according to claim 1, characterized in that: The iron salt is one or more of ferric citrate pentahydrate, ferric chloride or anhydrous ferric citrate.

9. The method for synthesizing maltol iron crystal form II according to claim 8, characterized in that: In the iron salt aqueous solution, the mass ratio of iron salt to water is 1:(3-5).

10. The method for synthesizing maltol iron crystal form II according to claim 1, characterized in that: The mass ratio of the maltol iron crystal form II seed to maltol is 1:(5-115).

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