Serial crystallization

Abstract

The present invention provides a method for purifying 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, comprising adding a single dose of acid to a stream containing crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide in a solvent, and continuously crystallizing 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide from the crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide while removing at least a fraction of the solvent, wherein the crystallization is carried out in a continuous reactor, and the continuous reactor is a plug flow reactor. During crystallization, at least three additional doses of acid are added to the continuous reactor.

Description

Technical Field

[0001] The present invention relates to a method for purifying 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide and to 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (hereinafter "the compound of the present invention") produced by such a process.

[0002] The present invention provides advantages over prior art processes for purifying this compound.

Background Art

[0003] The prior art purifies 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide using a batch reactor. The method in the prior art involves adding hydrochloric acid to the reaction mixture until the reaction mixture becomes turbid, adding a seed crystal for purifying the compound, and stirring the resulting slurry before adding additional hydrochloric acid. Next, the slurry is cooled overnight (e.g., to about 20 - 25 °C). The next day, the slurry is filtered, the filter cake is washed with methanol, and then dried in a vacuum oven. Such a process is described in US Patent Application Publication No. 2016 / 304438.

Summary of the Invention

[0004] Improvements in the purification of commercially useful compounds (such as the compound of the present invention) on an industrial scale are an ongoing objective.

[0005] The present invention is a method for purifying 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, comprising (i) adding one portion of an acid to a stream containing crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide in a solvent, (ii) Continuously crystallizing 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide from crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, along with the removal of at least the solvent fraction, wherein the crystallization is carried out in a continuous reactor, and the continuous reactor is a plug flow reactor. Includes, During the crystallization process, add at least three additional doses of acid to the continuous reactor. Regarding the method.

[0006] Therefore, the process is a continuous reactor process, and the reactor is a plug-flow reactor. Methods described herein using any type of continuous reactor are also disclosed. For example, a COBR (Continuous Oscillating Flow Baffle Reactor) or a Continuous Stirred Tank Reactor (CSTR) may be used in any of the methods described herein.

[0007] The method of the present invention is preferably carried out at a temperature between 20°C and 60°C, typically starting at about 60°C and then cooling to about 20°C. If the reaction mixture in which the crude compound of the present invention (before purification) is produced was at a higher temperature, further cooling will be required.

[0008] The acid used in the method may be a water-soluble inorganic acid, preferably selected from the group consisting of sulfuric acid, nitric acid, and hydrochloric acid. The acid is most preferably hydrochloric acid.

[0009] The acid in step (i) of the process may be added to the stream containing the crude compound of the present invention in an amount of 0.3 to 0.6 molar equivalents, 0.4 to 0.5 molar equivalents, or 0.45 molar equivalents relative to the compound of the present invention in the crude mixture.

[0010] At least three additional doses of acid may be added to the continuous reactor in amounts of 0.05 to 0.6 molar equivalents relative to the compound of the present invention in the crude mixture.

[0011] At least three doses of acid may be added to the continuous reactor in an amount between 0.1 and 0.5 molar equivalents relative to the compound of the present invention in the crude mixture.

[0012] More specifically, at least five additional doses of acid may be added to the continuous reactor, where, (i) The first of at least five additional doses of acid may be added to the continuous reactor in an amount of 0.1 to 0.2 molar equivalents relative to the compound of the present invention in the crude mixture. (ii) The second of at least five doses of acid may be added to the continuous reactor in an amount of 0.5 to 1.5 molar equivalents relative to the compound of the present invention in the crude mixture. (iii) The third of at least five doses of acid may be added to the continuous reactor in an amount of 0.5 to 1.5 molar equivalents relative to the compound of the present invention in the crude mixture. (iv) The fourth of at least five doses of acid may be added to the continuous reactor in an amount of 0.03 to 0.11 molar equivalents relative to the compound of the present invention in the crude mixture, and (v) The fifth of at least five doses of acid may be added to the continuous reactor in an amount of 0.1 to 0.5 molar equivalents relative to the compound of the present invention in the crude mixture.

[0013] In the method of the present invention, an additional at least five doses of acid may be added to the continuous reactor, where (i) The first of at least five additional doses of acid is: Full It may be added at a point between 9% and 19% of the residence time, and / or (ii) The second of at least five doses of acid, Full It may be added at a point between 31% and 41% of the residence time, and / or (iii) At least the third of five doses of acid, Full It may be added between 44% and 54% of the residence time, and / or (iv) At least five doses of the acid, the fourth dose, Full It may be added at a point between 61% and 71% of the residence time, and / or (v) The fifth portion of the acid for at least five portions may be added at a point between 84% and 94% of the residence time. Full The additional at least five portions of acid may be added to a continuous reactor, where

[0014] The additional at least five portions of acid may be added to a continuous reactor, where (i) The first portion of the additional at least five portions of acid may be added at a point between 13% and 16% of the residence time, and / or Full (ii) The second portion of the at least five portions of acid may be added at a point between 34.5% and 37.5% of the residence time, and / or (iii) The third portion of the at least five portions of acid may be added at a point between 48% and 51% of the residence time, and / or Full (iv) The fourth portion of the at least five portions of acid may be added at a point between 66% and 69% of the residence time, and / or (v) The fifth portion of the at least five portions of acid may be added at a point between 88% and 91% of the residence time. Full (v) The fifth portion of the at least five portions of acid may be added at a point between 88% and 91% of the residence time. (iv) The fourth portion of the at least five portions of acid may be added at a point between 66% and 69% of the residence time, and / or Full (v) The fifth portion of the at least five portions of acid may be added at a point between 88% and 91% of the residence time. / / This line seems to be a duplicate of the previous one in terms of the text. Maybe there's a mistake in the original? (v) The fifth portion of the at least five portions of acid may be added at a point between 88% and 91% of the residence time. Full (v) The fifth portion of the at least five portions of acid may be added at a point between 88% and 91% of the residence time.

[0015] The options (i) to (v) regarding the above timings may be preferably combined.

[0016] When adding the additional at least five portions of acid to a continuous reactor, the continuous reactor may be any type of continuous reactor. In particular, the continuous reactor may be one of a plug flow reactor, a COBR (Continuous Oscillatory Baffle Reactor), or a continuous stirred tank reactor (CSTR). In particular, the acid may be hydrochloric acid.

[0017] The time of the purification step is usually in the range of about 40 minutes to 3 hours, optionally 1 to 2 hours.

[0018] / / These two lines seem to be empty in the original. Not sure if there's a mistake. The total amount of acid added in steps (i) and (ii) of the method is preferably 1 to 1.4 molar equivalents, most preferably about 1.2 molar equivalents, relative to the crude compound of the present invention to be purified.

[0019] In the method, seed crystals may be added to the continuous reactor. The initial slurry of seed crystals is not a limiting factor. The seed crystals are preferably added to the continuous reactor either with the first portion of acid or after the first portion of acid and before at least an additional three portions of acid are added to the continuous reactor.

[0020] The first portion of acid is preferably added to the continuous reactor upon injection of the process stream.

[0021] The solvent used in the method may be any solvent for the crude compound of the present invention. For example, the solvent may include water, methanol, 2-methoxy-ethanol, or any mixture. Examples of additional suitable solvents include ethers such as diethyl ether, tetrahydrofuran, dioxane, or dimethoxyethane, alcohols such as methanol or ethanol, and water. Among these, alcohols, particularly methanol, or a mixture of water and one or more alcohols are preferred.

[0022] In the method of the present invention, the solvent is optionally preferably removed by (i) distillation or (ii) azeotropic distillation, which may be carried out under reduced pressure.

[0023] The crystallization step may be carried out in one or more crystallization apparatuses, and preferably, the crude compound of the present invention is fed to the crystallization apparatus at a constant rate. The crystalline compound of the present invention is preferably recovered at a constant rate, more preferably at a rate such that the volume load of the crystallization apparatus is kept constant.

[0024] According to the present invention, the acid may be added (at each stage and / or overall) until a specific pH is reached. The overall pH may be about pH 2 to 8, preferably 5 to 7.

[0025] In the present invention, the acid in step (i) may be added to a stream containing the crude compound of the present invention until the stream becomes supersaturated with respect to the crude compound of the present invention.

[0026] In one embodiment of the method of the present invention, each of the second to fourth additions of the additional at least five doses of acid may be added at intervals of no more than 20% of the time between the preceding two acid additions. Each interval between the additions of the divided acid is preferably between 5 and 15 minutes, more preferably between 6 and 12 minutes. The intervals between the first and second additions of the additional at least five doses of acid and between the fourth and fifth additions of the divided acid may be similar and no more than 10% of the time. Preferably, the interval between the third and fourth additions of the additional at least five doses of acid is the shortest interval between any two acid additions.

[0027] The present invention also provides purified compounds produced by the method of the present invention.

[0028] The purification method of the present invention appears to precede, in some way, the formation of the compound of the present invention itself, and although this formation step is not required, it may be part of the claimed method of the present invention. In one example of the formation method, 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide is mixed with acetic anhydride / acetic acid to form a slurry. Next, this slurry is heated to about 60°C, an acidic catalyst is added to the reactants, and the reaction temperature is maintained between 65°C and 85°C. In the final step, a deacetylating agent is added before the product is offered for purification. The catalyst may be a sulfonic acid.

[0029] The present invention is a continuous crystallization method, which is fundamentally different from batch crystallization (in a batch reactor). In the former, supersaturation at a given point in the reactor is constant over time. In other words, supersaturation is a function of distance from the reactor inlet. In the latter, supersaturation is a function of time. Therefore, it was neither anticipated nor foreseen that the prior art batch crystallization would be competitively and industrially transitionable to a continuous method (plug-flow reactor). In fact, various methodologies for the process in a continuous process (except for the method of the present invention) were unsuitable. However, due to the need for production capacity and current capacity constraints, there was a need to find an alternative process for purifying aryl iodide compounds, and the inventors solved this problem by transitioning to a continuous process to establish the method of the present invention. The present invention has been found to have advantages in terms of reduced footprint, low investment cost, reproducibility, and crystal filtration behavior. [Modes for carrying out the invention]

[0030] Crystals obtained using the method of the present invention were found to have a different shape from those obtained using previous methods (see Figure 1: top is the method of the present invention; bottom is the previous method). Crystals from the present invention were easier to separate from the mother liquor, pre-dried, and for which salts and by-products could be removed. Crystals from the present invention were also found to be less prone to "scaling," i.e., crystal growth on the reactor walls, which can lead to reactor malfunction over time. From an industrial standpoint, this is advantageous because it means that less investment is required to obtain the specified filtration capacity.

[0031] This invention relates to the purification of the compound of the present invention by reaction crystallization in a continuous manner. For this reason, the method is highly specific and therefore not suitable for other iodide compounds, even if similar.

[0032] In preliminary tests prior to the present invention, it was explored how hydrochloric acid could be added to obtain crystals that are easy to handle during filtration, washing, and drying. For quick and easy crystallization, it was thought that adding the smallest possible amount of hydrochloric acid would be beneficial. However, this could lead to higher supersaturation, which could subsequently result in the formation of crystals that are difficult to handle, and there is also a high risk of scaling on the inside of the tube walls in the plug flow reactor. In some experiments, all hydrochloric acid was added in a single step. Such crystallization was uncontrollable due to high supersaturation. In the method of the present invention, hydrochloric acid is added in multiple portions, as described in the following examples. [Examples]

[0033] The present invention will be described with reference to the following examples. In the following examples, HCl is used, but as described above, any water-soluble inorganic acid may be used.

[0034] [Example 1] The total amount of hydrochloric acid used was 1.2 molar equivalents relative to the compound of the present invention to be purified.

[0035] In the first experiment, "Package," eight experiments were conducted, dividing the amount of hydrochloric acid into four portions. The first portion (0.45 molar equivalents) was added at injection at 60°C. The seed crystal slurry (1.7 w / w%) relative to the total amount of crystallized compound) was added 3.4 minutes after injection. The second portion of hydrochloric acid (0.15 molar equivalents) was added 6.6 minutes after injection. The third portion (0.20 molar equivalents) and the fourth portion (0.40 molar equivalents) were added 16.3 minutes and 25.8 minutes after injection, respectively. Cooling (from 60°C to 20°C) was started 34.6 minutes after injection and took 12.4 minutes. Therefore, the total time for hydrochloric acid addition was 25.8 minutes, but the total process time was 47.0 minutes. The COBR reactor was operated with an amplitude of 40 mm and a frequency of 1.5 Hz.

[0036] In the following experiments, different combinations of amplitude and frequency were investigated. In some of these experiments, the concentration (not the amount) of hydrochloric acid in the fourth minute was reduced from 17.5% to 8.75%.

[0037] In the next experiment, two things were changed. First, the frequency was reduced from 1.5 Hz to 1.3 Hz. Second, the concentration (not the amount) of hydrochloric acid in the fourth sample was reduced from 17.5% to 8.75%. The frequency was further reduced from 1.3 Hz to 1.2 Hz, and then increased again. The combination of a frequency of 1.5 Hz and an amplitude of 30 mm was also tried.

[0038] Overall, the product quality of the crystals and the filtration behavior were within acceptable limits. Some scaling was observed around the third and fourth additions of hydrochloric acid. However, this will almost certainly be resolved when moving from laboratory scale to industrial scale. In the latter case, the much larger diameter of the tubes will eliminate the supersaturation in the liquid caused by the addition of hydrochloric acid rather than crystallization at the tube walls.

[0039] [Example 2] Some experiments were conducted in a second "package." In all experiments, the frequency and amplitude were 1.3 Hz and 35 mm, respectively.

[0040] In all experiments, the amount of seed crystal slurry was 2.0 w / w%. Cooling from 60°C to 20°C was performed in a CSTR reactor installed immediately following the outlet of the COBR reactor. As with frequency and amplitude, these parameters were standard and were not deemed decisive for the method of the present invention. The total amount of hydrochloric acid added to the COBR reactor was 1.0 or 1.2 molar equivalents relative to the compound being purified. In all experiments, the hydrochloric acid was divided into six portions (unlike the first "package" in which the hydrochloric acid was divided into four portions).

[0041] In the first experiment, the first dose (0.45 molar equivalents) was added at the time of injection. The seed crystal slurry was added 2.8 minutes after injection. The second dose of hydrochloric acid (0.15 molar equivalents) was added 7.6 minutes after injection. The third dose (0.10 molar equivalents) was added 19.1 minutes after injection, the fourth dose (0.10 molar equivalents) was added 26.2 minutes after injection, the fifth dose (0.20 molar equivalents) was added 35.7 minutes after injection, and the sixth dose (0.20 molar equivalents) was added 43.3 minutes after injection. The time at the outlet (from COBR to CSTR) was 52.8 minutes.

[0042] The differences between Experiment 1 and Experiment 2 are listed below in bold (translator's note: they are underlined in the translated text).

[0043] In the second experiment, the first portion ( 0.48 The molar equivalent was added at the time of injection. The seed crystal slurry was added 2.8 minutes after injection. The second dose of hydrochloric acid ( 0.18 The molar equivalent was added 7.6 minutes after the injection. The third dose (0.10 molar equivalent) was added 19.1 minutes after the injection, the fourth dose (0.10 molar equivalent) was added 26.2 minutes after the injection, and the fifth dose ( 0.11 Add the molar equivalent 35.7 minutes after the injection, and the 6th dose ( 0.23 The molar equivalent was added 43.3 minutes after injection. The time at the outlet (from COBR to CSTR) was 52.8 minutes.

[0044] The differences between Experiment 2 and Experiment 3 are listed below in bold (translator's note: they are underlined in the translated text).

[0045] In the third experiment, the first portion ( 0.45 The molar equivalent was added at the time of injection. The seed crystal slurry was added 2.8 minutes after injection. The second dose of hydrochloric acid ( 0.15 The molar equivalent was added 7.6 minutes after the injection. The third dose (0.10 molar equivalent) was added 19.1 minutes after the injection, the fourth dose (0.10 molar equivalent) was added 26.2 minutes after the injection, and the fifth dose ( 0.10 Add the molar equivalent 35.7 minutes after the injection, and the 6th dose ( 0.10The molar equivalent was added 43.3 minutes after injection. Note that the total amount of hydrochloric acid was 1.0 molar equivalent (not 1.2). The time at the outlet (from COBR to CSTR) was 52.8 minutes.

[0046] The differences between Experiment 3 and Experiment 4 are listed below in bold (Translator's note: Underlined in the translated text).

[0047] In the fourth experiment, the first dose (0.45 molar equivalent) was added at the time of injection. The seed crystal slurry was added 2.8 minutes after injection. The second dose of hydrochloric acid (0.15 molar equivalent) was added 7.6 minutes after injection. The third dose (0.10 molar equivalent) was added 19.1 minutes after injection, the fourth dose (0.10 molar equivalent) was added 26.2 minutes after injection, and the fifth dose ( 0.08 Add the molar equivalent 35.7 minutes after the injection, and the 6th dose ( 0.12 The molar equivalent was added 43.3 minutes after injection. Note that the total amount of hydrochloric acid was 1.0 molar equivalent (not 1.2). The time at the outlet (from COBR to CSTR) was 52.8 minutes.

[0048] The differences between Experiment 4 and Experiment 5 are listed below in bold (Translator's note: Underlined in the translated text).

[0049] In the fifth experiment, the first dose (0.45 molar equivalents) was added at the time of injection. The seed crystal slurry was added 2.8 minutes after injection. The second dose of hydrochloric acid (0.15 molar equivalents) was added 7.6 minutes after injection. The third dose (0.10 molar equivalents) was added 19.1 minutes after injection, the fourth dose (0.10 molar equivalents) was added 26.2 minutes after injection, the fifth dose (0.08 molar equivalents) was added 35.7 minutes after injection, and the sixth dose ( 0.16 The molar equivalent was added 43.3 minutes after injection. Note that the total amount of hydrochloric acid was 1.04 molar equivalents (not 1.2). The time at the outlet (from COBR to CSTR) was 52.8 minutes.

[0050] The differences between Experiment 5 and Experiment 6 are listed below in bold (Translator's note: Underlined in the translated text).

[0051] In the sixth experiment, the first dose (0.45 molar equivalents) was added at the time of injection. The seed crystal slurry was added 2.8 minutes after injection. The second dose of hydrochloric acid (0.15 molar equivalents) was added 7.6 minutes after injection. The third dose (0.10 molar equivalents) was added 19.1 minutes after injection, the fourth dose (0.10 molar equivalents) was added 26.2 minutes after injection, the fifth dose (0.08 molar equivalents) was added 35.7 minutes after injection, and the sixth dose ( 0.32 The molar equivalent was added 43.3 minutes after injection. Note that the total amount of hydrochloric acid in this case was 1.2 molar equivalents. The time at the outlet (from COBR to CSTR) was 52.8 minutes.

[0052] The differences between Experiment 6 and Experiment 7 are listed below in bold (Translator's note: Underlined in the translated text).

[0053] In the seventh experiment, the first dose (0.45 molar equivalents) was added at the time of injection. The seed crystal slurry was added 2.8 minutes after injection. The second dose of hydrochloric acid (0.15 molar equivalents) was added 7.6 minutes after injection. The third dose (0.10 molar equivalents) was added 19.1 minutes after injection, the fourth dose (0.10 molar equivalents) was added 26.2 minutes after injection, the fifth dose (0.08 molar equivalents) was added 35.7 minutes after injection, and the sixth dose (0.32 molar equivalents) was added at the time of injection. 47.2 It was added after minutes. Note that the total amount of hydrochloric acid in this case was 1.2 molar equivalents. The time at the outlet (from COBR to CSTR) was 52.8 minutes.

[0054] The differences between Experiment 7 and Experiment 8 are listed below in bold (Translator's note: Underlined in the translated text).

[0055] In the eighth experiment, the first dose (0.45 molar equivalents) was added at the time of injection. Seed crystal slurry (3.1 w / w% instead of 2.0 w / w%) was added 2.8 minutes after injection. The second dose of hydrochloric acid (0.15 molar equivalents) was added 7.6 minutes after injection. The third dose (0.10 molar equivalents) was added 19.1 minutes after injection, the fourth dose (0.10 molar equivalents) was added 26.2 minutes after injection, the fifth dose (0.08 molar equivalents) was added 35.7 minutes after injection, and the sixth dose (0.32 molar equivalents) was added at the time of injection. 47.2 It was added after minutes. Note that the total amount of hydrochloric acid in this case was 1.2 molar equivalents. The time at the outlet (from COBR to CSTR) was 52.8 minutes.

[0056] Scaling near the point of the sixth hydrochloric acid addition was slightly reduced by extending the time between the fifth and sixth hydrochloric acid additions. The filtration behavior of the crystals obtained above was the same as in the previous experiment. Surprisingly, the liquid content before drying was now somewhat lower than that of the crystals from the product. Therefore, the crystals were examined by scanning electron microscopy (SEM). The crystals were found to have a slightly different shape from those from the product (see Figure 1). Pre-drying (by blowing nitrogen) of the crystals from this experiment was easier than that of the crystals from the product. The salt content of these crystals was also lower (≤0.2 w / w%). [Brief explanation of the drawing]

[0057]

Figure 1

[0058] The product quality of the crystals was the same as that of the first "package." The filtration behavior was generally slightly improved, and drying these crystals was even easier. The scaling observed in several hydrochloric acid additions in "package" 1 disappeared in many experiments with the "second package."

[0059] The examples were conducted on a laboratory scale, and it will be understood by those skilled in the art that the conditions used may be adaptable when implementing the invention on an industrial scale. For example, smaller fractions of acid may be used. The present invention includes the following embodiments. <1> A method for purifying 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, (i) Add a single dose of acid to a stream containing crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide in the solvent. (ii) Continuously crystallizing 5-acetamide-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide from the crude 5-acetamide-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, along with the removal of at least the solvent fraction, wherein the crystallization is carried out in a continuous reactor, and the continuous reactor is a plug flow reactor. Includes, During the crystallization process, add at least three additional doses of acid to the continuous reactor. method. <2> The acid in step (i) is added to the stream containing the crude 5-acetamide-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide in an amount of 0.3 to 0.6 molar equivalents, 0.4 to 0.5 molar equivalents, or about 0.45 molar equivalents relative to the crude 5-acetamide-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide. <1> Methods used. <3> The aforementioned at least three doses of acid are each added to the continuous reactor in an amount of 0.05 to 0.6 molar equivalents relative to crude 5-acetamide-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide. <1> or <2> Methods used. <4> Each of the three or more acids is added to the continuous reactor in an amount between 0.1 and 0.5 molar equivalents relative to the crude 5-acetamide-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide. <1> ~ <3> One of the methods described above. <5> The aforementioned additional at least three doses of acid are additional at least five doses of acid, (i) The first of at least five doses of acid is added to the continuous reactor in an amount of 0.1 to 0.2 molar equivalents relative to the crude 5-acetamide-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, (ii) The second of the five doses of acid is added to the continuous reactor in an amount of 0.5 to 1.5 molar equivalents relative to the crude 5-acetamide-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, (iii) The third of the five doses of acid is added to the continuous reactor in an amount of 0.5 to 1.5 molar equivalents relative to the crude 5-acetamide-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, (iv) The fourth of the five doses of acid is added to the continuous reactor in an amount of 0.03 to 0.11 molar equivalents relative to the crude 5-acetamide-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, and (v) The fifth of the five doses of acid is added to the continuous reactor in an amount of 0.1 to 0.5 molar equivalents relative to the crude 5-acetamide-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide. <1> ~ <4> One of the methods described above. <6> The aforementioned additional at least three doses of acid are additional at least five doses of acid, (i) The first of the five doses of acid is Full It is added at a point between 9% and 19% of the dwell time, and / or (ii) The second of the five doses of acid mentioned above, Full It is added between 31% and 41% of the residence time, and / or (iii) The third of the five doses of acid mentioned above, Full It is added between 44% and 54% of the dwell time, and / or (iv) The fourth of the five doses of acid mentioned above, Full It is added between 61% and 71% of the residence time, and / or (v) The fifth of the five additional doses of acid, Full It is added between 84% and 94% of the residence time. <1> ~ <5> One of the methods described above. <7> The total amount of acid added in steps (i) and (ii) of step 1 is 1 to 1.2 molar equivalents relative to the crude 5-acetamide-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide. <1> ~ <6> One of the methods described above. <8> Seed crystals are added to the continuous reactor. <1> ~ <7> One of the methods described above. <9> The seed crystal is added to the continuous reactor either together with the acid in step i) or after the acid and before the additional at least five doses of acid are added to the continuous reactor. <1> ~ <8> One of the methods described above. <10> The first dose of the acid is added to the continuous reactor when the process flow is injected. <1> ~ <9> One of the methods described above. <11> The solvent is removed by (i) distillation or (ii) azeotropic distillation. <1> ~ <10> One of the methods described above. <12> The crystallization step is carried out in one or more crystallization apparatus, preferably the crude 5-acetamide-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide is supplied to the crystallization apparatus at a constant rate. <1> ~ <11> One of the methods described above. <13> Crystalline 5-acetamide-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide is recovered at a constant rate, preferably at a rate that keeps the volume load of the crystallization apparatus constant. <1> ~ <12> One of the methods described above. <14> The aforementioned acid (i) It is a water-soluble inorganic acid, or (ii) Selected from the group consisting of sulfuric acid, nitric acid, and hydrochloric acid, or (iii) It is hydrochloric acid, <1> ~ <13> One of the methods described above. <15> <1> ~ <14> Purified 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, produced by any of the methods described in the following.

Claims

1. A method for purifying 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, (i) Add a single dose of acid to a stream containing crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide in the solvent. (ii) Continuously crystallizing 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide from the crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, along with the removal of at least the solvent fraction, wherein the crystallization is carried out in a continuous reactor, and the continuous reactor is a plug flow reactor. Includes, During the crystallization process, add at least three additional doses of acid to the continuous reactor. The aforementioned additional at least three doses of acid are additional at least five doses of acid, During the crystallization process, at least five additional doses of acid were added separately to the continuous reactor. (i) The first of the five doses of acid is added at a point between 9% and 19% of the total residence time, and / or (ii) The second of the five doses of acid is added at a point between 31% and 41% of the total residence time, and / or (iii) The third of the five doses of acid is added at a point between 44% and 54% of the total residence time, and / or (iv) The fourth of the five doses of acid is added at a time between 61% and 71% of the total residence time, and / or (v) The fifth of the five additional doses of acid is added between 84% and 94% of the total residence time. method.

2. The method according to claim 1, wherein the acid in step (i) is added to the stream containing the crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide in an amount of 0.3 to 0.6 molar equivalents, 0.4 to 0.5 molar equivalents, or 0.45 molar equivalents relative to the crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.

3. The method according to claim 1 or claim 2, wherein at least five portions of the acid are each added to the continuous reactor in an amount of 0.05 to 0.6 molar equivalents relative to crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.

4. The method according to any one of claims 1 to 3, wherein each of the at least five doses of acid is added to the continuous reactor in an amount between 0.1 and 0.5 molar equivalents relative to the crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.

5. (i) The first of at least five doses of acid is added to the continuous reactor in an amount of 0.1 to 0.2 molar equivalents relative to the crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, (ii) The second of the five doses of acid is added to the continuous reactor in an amount of 0.5 to 1.5 molar equivalents relative to the crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, (iii) The third of the five doses of acid is added to the continuous reactor in an amount of 0.5 to 1.5 molar equivalents relative to the crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide. (iv) The fourth of the five doses of acid is added to the continuous reactor in an amount of 0.03 to 0.11 molar equivalents relative to the crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, and (v) The fifth of the five doses of acid is added to the continuous reactor in an amount of 0.1 to 0.5 molar equivalents relative to the crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide. The method according to any one of claims 1 to 4.

6. The method according to any one of claims 1 to 5, wherein the total amount of acid added in steps (i) and (ii) of claim 1 is 1 to 1.2 molar equivalents relative to the crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.

7. The method according to any one of claims 1 to 6, wherein the seed crystal is added to the continuous reactor.

8. The method according to any one of claims 1 to 7, wherein the seed crystal is added to the continuous reactor together with the acid in step (i) or after the acid and before the additional at least five doses of acid are added to the continuous reactor.

9. The method according to any one of claims 1 to 8, wherein the first portion of the acid in step (i) is added to the continuous reactor when the process flow is injected.

10. The method according to any one of claims 1 to 9, wherein the solvent is removed by (i) distillation or (ii) azeotropic distillation.

11. The method according to any one of claims 1 to 10, wherein the crystallization step is carried out in one or more crystallization apparatuses.

12. The method according to claim 11, wherein the crude 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide is supplied to the crystallization apparatus at a constant rate.

13. The method according to claim 11 or 12, wherein crystalline 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide is recovered at a constant rate.

14. The method according to claim 13, wherein crystalline 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide is recovered at a rate that keeps the volumetric load of the crystallization apparatus constant.

15. The aforementioned acid (i) It is a water-soluble inorganic acid, or (ii) Selected from the group consisting of sulfuric acid, nitric acid, and hydrochloric acid, or (iii) It is hydrochloric acid. The method according to any one of claims 1 to 14.

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