Preparation method of iodixanol impurity G

Abstract

The invention discloses a preparation method of iodixanol impurity G, and relates to the field of chemical synthesis, which comprises the following steps: reacting a compound of formula 1 with 1-chloro-2, 3-propylene glycol to generate a compound of formula 2, cyclizing, acylating and alcoholyzing the compound of formula 2 to generate a compound of formula 3, brominating the compound of formula 3 to generate a compound of formula 4, reacting the compound of formula 4 with the compound of formula 1 to generate a compound of formula 5, the impurity is the iodixanol impurity. The invention provides the synthesis method of the iodixanol impurity G, so that the production mechanism of the iodixanol impurity G is more perfect in the iodixanol synthesis process, and the method for synthesizing the iodixanol impurity G is simpler and more efficient.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, in particular to a method for preparing an iodixanol impurity G. Background Art

[0002] Iodixanol is an important product in the series of iodine-based contrast agents for injection. It is suitable for spinal canal, cardiovascular and cerebrovascular, and intravenous urography. Its working principle is to combine iodine absorption of X-rays in human blood vessels or tissues to affect the display. Therefore, the quality and impurities of iodixanol raw materials have extremely strict requirements. In order to ensure the safety of people's medication, it is very meaningful to study the impurities in iodixanol. The structure of impurity G in iodixanol in the European Pharmacopoeia is as follows:

[0003]

[0004] The liquid phase purity percentage of the iodixanol impurity G in the reaction solution of iodixanol synthesized by different methods is different, generally less than 0.5%. However, too high a percentage will affect the purification yield of iodixanol. Therefore, it is very meaningful to study the generation of iodixanol impurities.

[0005] At present, the mainstream route for the synthesis of iodixanol is to condense iodixanol hydrolyzate (i.e., iodixanol impurity B recorded in the European Pharmacopoeia) with epichlorohydrin under alkaline conditions to produce iodixanol. The synthesis route is as follows:

[0006]

[0007] Among them, there are two main pathways for the production of iodixanol impurity G: one is the iodixanol hydrolyzate pathway, where iodixanol hydrolyzate is produced under alkaline conditions and a certain temperature; the other is the iodixanol pathway, where iodixanol is produced under alkaline conditions and a certain temperature: The specific two production pathways have the following chemical reaction formulas:

[0008] 1) Chemical synthesis route of impurity G from iodixanol hydrolysate (i.e., iodixanol impurity B recorded in the European Pharmacopoeia):

[0009]

[0010] 2) Chemical synthesis route of iodixanol to produce impurity G:

[0011]

[0012] In practice, when iodixanol is used to directly prepare iodixanol impurity G through alkaline hydrolysis, the acetyl group on the amino group before the ring closure is prone to cleavage of the amide bond at high temperature, and mainly generates iodixanol impurity F. Therefore, most synthesizers first prepare iodixanol impurity F with higher purity, then acetylate impurity F with an acetylating agent, and then control alkaline hydrolysis under certain conditions. However, the control of this condition is extremely harsh, and iodixanol impurity G is easy to turn into impurity iodixanol F again, and the required iodixanol impurity G cannot be obtained. Among them, patent CN113968826A reports the synthesis of impurity G through iodixanol. Patent CN113968826A reports the route for synthesizing impurity G as follows:

[0013]

[0014] However, there are few reports on the route of synthesizing impurity G via iodixanol hydrolyzate (iodixanol impurity B). Summary of the invention

[0015] The purpose of the present invention is to solve at least one of the technical problems existing in the prior art and to provide a method for preparing iodixanol impurity G.

[0016] The technical solution of the present invention is as follows:

[0017] A method for preparing an iodixanol impurity G comprises reacting a compound of formula 1 with 1-chloro-2,3-propylene glycol to generate a compound of formula 2, cyclizing the compound of formula 2 to generate a compound of formula 3, brominating the compound of formula 3 to generate a compound of formula 4, and reacting the compound of formula 4 with the compound of formula 1 to generate a compound of formula 5, i.e., an iodixanol impurity;

[0018] The structural formula of the compound of formula 1 is:

[0019] The structural formula of the compound of formula 2 is:

[0020] The structural formula of the compound of formula 3 is:

[0021] The structural formula of the compound of formula 4 is:

[0022] The structural formula of the compound of formula 5 is:

[0023] As a preferred embodiment of the present invention, the synthesis method of the compound of formula 2 is as follows: ethylene glycol methyl ether is used as a solvent, sodium methoxide is used as a nitrogen alkylating agent, and the compound of formula 1 is reacted, followed by acid adjustment, concentration, dissolution, decolorization resin desalination, concentration and drying to obtain the compound.

[0024] As a preferred embodiment of the present invention, the synthesis method of the compound of formula 3 is as follows: a strong base, water and a compound of formula 2 are heated to produce a cyclization reaction, and then concentrated, desalted with methanol, dissolved, desalted with resin, concentrated again, slurried with methanol, filtered and dried, acylated, and alcoholyzed to obtain the compound.

[0025] As a preferred embodiment of the present invention, the cyclization reaction temperature is 70-80° C., and the reaction time is 16 to 24 hours.

[0026] As a preferred embodiment of the present invention, the temperature of methanol desalination is -5 to 5°C.

[0027] As a preferred embodiment of the present invention, the amount of methanol in the pulping is 10 to 20 times the mass of the compound of formula 2.

[0028] As a preferred embodiment of the present invention, the synthesis method of the compound of formula 5 is as follows: after dissolving purified water, caustic soda flakes and the compound of formula 1, reacting with the compound of formula 4 under the protection of boric acid, adjusting the acid, passing through a column, collecting the corresponding fractions, concentrating under reduced pressure until a large amount of solid precipitates, filtering, and drying to obtain a filter cake.

[0029] As a preferred embodiment of the present invention, the reaction temperature of the compound of formula 1 and the compound of formula 4 is 0-10°C.

[0030] As a preferred embodiment of the present invention, the compound of formula 4 is 0.25 to 0.75 equivalent of the compound of formula 1.

[0031] The synthetic route is as follows:

[0032]

[0033] The invention has the beneficial effects that: the existing methods for synthesizing impurity G all use iodixanol to directly cyclize with a strong base, and in the process of cyclization, a small amount of iodixanol cannot react and remains in impurity F, and after impurity F is acetylated and then hydrolyzed, a small amount of iodixanol will exist in the generated impurity G, and impurity G and iodixanol are not easy to separate in the liquid phase, which will cause impurity G to be impure, and in addition, after impurity F is acetylated and then hydrolyzed, the reaction is not easy to control, and impurity G is easily converted back to impurity F. The invention provides a method for synthesizing iodixanol impurity G, so that its generation mechanism in the process of iodixanol synthesis is more perfect, and the method for synthesizing iodixanol impurity G becomes simpler and more efficient. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is the liquid phase detection spectrum of iodixanol;

[0035] Figure 2 This is the liquid phase detection spectrum of the iodixanol impurity G in Example 1. DETAILED DESCRIPTION

[0036] The invention relates to a method for synthesizing an iodixanol impurity G, wherein the compound of formula 1 (iodixanol impurity B) and 1-chloro-2,3-propanediol react to generate a compound of formula 2 (iodixanol impurity A), the compound of formula 2 (iodixanol impurity A) undergoes cyclization, acylation, and alcoholysis to generate a compound of formula 3 (iodixanol impurity G precursor 1), the compound of formula 3 (iodixanol impurity G precursor 1) undergoes bromination to generate a compound of formula 4 (iodixanol impurity G precursor 2), the compound of formula 4 (iodixanol impurity G precursor 2) and the compound of formula 1 (iodixanol impurity B) react to generate a compound of formula 5 (iodixanol impurity G), and for the convenience of description, the key compound in the reaction process of iodixanol synthesis is referred to as a compound of formula 5 in the subsequent content. Preferably, the method comprises the following steps:

[0037] (1) Synthesis of compound of formula 2

[0038] The compound of formula 2 is obtained by using ethylene glycol methyl ether as solvent and sodium methoxide as nitrogen alkylating agent to react with formula 1, adjusting acid, concentrating, dissolving, removing salt with decolorizing resin, concentrating and drying.

[0039] (2) Synthesis of compound of formula 3

[0040] A strong base, water and the compound of formula 2 are heated to cause a cyclization reaction, and the reaction is concentrated, desalted with methanol, dissolved, desalted with resin, concentrated again, slurried with methanol, filtered and dried, acylated, alcoholyzed, filtered and dried to obtain a compound of formula 3, wherein the cyclization reaction temperature is 70-80°C, the reaction time is 16-24 hours, the methanol desalting temperature is -5 to 5°C, the resin is desalted, and the amount of methanol for slurrying is 10-20 times the mass of the compound of formula 2.

[0041] (3) Synthesis of compound of formula 4

[0042] Bromic acid, water and the compound of formula 3 are subjected to bromination reaction, and then desalted with concentrated methanol after alkali adjustment and resin desalination, wherein the water is 1-5 times the weight of the compound of formula 3, the concentration of bromic acid is about 40wt%, the reaction temperature is 60-80°C, the reaction time is 8-16 hours, the methanol desalination temperature is -5 to 5°C, and the volume of anionic resin in the resin desalination is 1:2.

[0043] (4) Synthesis of compound of formula 5

[0044] After the purified water, caustic soda flakes and the compound of formula 1 are dissolved, they are reacted with the compound of formula 4 under the protection of boric acid, and the acid is adjusted and passed through a column, and the corresponding fractions are collected, and the mixture is concentrated under reduced pressure until a large amount of solid is precipitated, filtered and dried to obtain a filter cake, i.e., the compound of formula 5. The reaction temperature of the compound of formula 1 and the compound of formula 4 is 0-10°C, and the compound of formula 4 is 0.25-0.75 equivalents of the compound of formula 1, preferably 0.35-0.65, and more preferably 0.45-0.55; the equivalents of boric acid and the compound of formula 1 are 0.7-1.3, preferably 0.8-1.2, and more preferably 0.9-1.1, and the strong base is 1.6-2.4 equivalents of the compound of formula 1.

[0045] The technical solution of the present invention is further described below with reference to specific embodiments.

[0046] Example 1

[0047] (1) Synthesis of compound of formula 2

[0048] Put 90g of ethylene glycol monomethyl ether and 24g of sodium methoxide into a reaction bottle, stir evenly, put in 80g of compound 1 (iohexol hydrolyzate), heat to 55℃, stir to dissolve, evaporate an appropriate amount of methanol, cool the solution to 20℃, drop 14g of 1-chloro-2,3-propanediol, and keep warm for 76h. Add concentrated hydrochloric acid to adjust the pH to 4-6, stir for 1h. Remove 80g of ethylene glycol monomethyl ether by vacuum distillation, add 80g of water and vacuum distill ethylene glycol monomethyl ether until the water evaporated reaches 80g, then end the distillation. Add 170g of water and stir, heat to 55-65℃ to dissolve, add 5g of activated carbon and decolorize at 55-65℃ for 2h, filter, wash the reaction bottle and filter cake with 30g of water, cool the filtrate to 25℃, combine and pass through anion and cation resins until the conductivity of the feed solution is less than 100us / cm, wash the anion and cation resins with deionized water until there is no fluorescence, combine the filtrates, and concentrate under reduced pressure until there is basically no fraction flowing out, to obtain 64g of compound 2 (iohexol).

[0049] (2) Synthesis of compound of formula 3

[0050] 30g of strong base (sodium hydroxide or potassium hydroxide) and 1L of deionized water were added to a reaction bottle, 50g of the compound of formula 2 was added and stirred to dissolve, the temperature was raised to 75°C for reaction for 20 hours, the reaction solution was concentrated to dryness, 1000mL of methanol was added to dissolve and filter to remove salt, the filtrate was concentrated to dryness, 100ml of deionized water was added to pass through anion and cation resin for desalination until the conductivity of the feed solution was <20us / cm, the desalted feed solution was concentrated to dryness under reduced pressure, 1200ml of anhydrous methanol was added for pulping, filtered, dried, and put into 1g of concentrated sulfuric acid and 100g of acetic anhydride, reacted for 2 hours, distilled under reduced pressure, 200g of methanol was added to reflux, dichloromethane was added until solid precipitated, filtered and dried to obtain 29g of the compound of formula 3.

[0051] (3) Synthesis of compound of formula 4

[0052] 36 g of 40% bromic acid and 50 g of deionized water were added to a reaction flask, and 26 g of the compound of formula 3 was added to the reactor. After the addition was completed, the internal temperature was controlled to 70°C for reaction. TLC detected that the raw materials had reacted. The pH was adjusted to 6 with liquid alkali, and the reaction solution was concentrated to dryness. 500 mL of methanol was added to dissolve the clear solution, and the salt was removed by filtration at 0°C. The filtrate was concentrated to dryness, and 100 ml of deionized water was added to pass through anion and cation resins for desalination (anion resin volume: cation resin volume = 1:2) until the conductivity of the feed solution was <20 us / cm. The desalted feed solution was concentrated to dryness under reduced pressure to obtain 23 g of the compound of formula 4.

[0053] (4) Synthesis of compound of formula 5

[0054] 25 ml of purified water and 2.1 g of caustic soda flakes were added to a reaction flask, stirred to dissolve, 20 g of compound 1 was added to a three-necked reaction flask, and after the solid was completely dissolved, the temperature was lowered to 5°C within T, 2.0 g of boric acid was added, and stirred for 24 h, 10 g of compound 4 was added, and the temperature was controlled within 5°C within T, and the temperature was controlled within 0-10°C to react for 100 h. After TLC detection, the reaction of compound 4 was complete, the pH was adjusted to 6, and the column was passed, and the corresponding fractions were collected, and the reduced pressure was concentrated until a large amount of solid precipitated, and filtered and dried to obtain 10 g of filter cake (compound 5), the purity of which was 93.7% by liquid phase detection, and the liquid phase detection spectrum of iodixanol impurity G ( Figure 2 ) and iodixanol liquid phase detection spectrum ( Figure 1 ) (Note: Figure 2 The peak time of 25.457 min is the first group of peaks of iodixanol impurity G, and the peak time of 32.283 min is the second group of peaks of iodixanol impurity G. Figure 1 The peak time of 26.553min is the first group of peaks of iodixanol, and the peak time of 29.977min is the second group of peaks of iodixanol). The detection method of iodixanol and iodixanol impurity G is (the detection method is optimized according to the European Pharmacopoeia):

[0055] Chromatographic column: C 18 Silica gel bonded chromatographic column 0.25*4.6

[0056] Mobile phase A: water, mobile phase B: acetonitrile: water = 1:1

[0057] Elution procedure:

[0058] Time (min) Mobile phase A (%) Mobile phase B (%) 0-3 94 6 3-33 94→80 6→20 33-73 80→0 20→100 73-83 0→94 100→6 83.1-92 94→94 6

[0059] Figure 1 and Figure 2From the comparison of the elution time, it can be seen that the first main peak of iodixanol impurity G and iodixanol are eluted together in the liquid phase, and the second main peak of iodixanol impurity G is eluted next to iodixanol. In order to ensure the safety of medication and reasonably control the impurity G in iodixanol, it is particularly important to study the generation mechanism of iodixanol impurity G in iodixanol.

[0060] Under the premise that no conflict occurs, those skilled in the art may freely combine and superimpose the above-mentioned additional technical features.

[0061] The above-mentioned embodiments only express the preferred implementation modes of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. It should be pointed out that, for ordinary technicians in this field, various other corresponding changes and deformations can be made according to the technical solutions and concepts described above, and all these changes and deformations should fall within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing iodixanol impurity G, characterized in that: The compound of formula 1 is reacted with 1-chloro-2,3-propanediol to generate the compound of formula 2, the compound of formula 2 is cyclized, acylated, and alcoholyzed to generate the compound of formula 3, the compound of formula 3 is brominated to generate the compound of formula 4, the compound of formula 4 is reacted with the compound of formula 1 to generate the compound of formula 5, i.e., the iodixanol impurity; The structural formula of the compound of formula 1 is: The structural formula of the compound of formula 2 is: The structural formula of the compound of formula 3 is: The structural formula of the compound of formula 4 is: The structural formula of the compound of formula 5 is:

2. The method for preparing an iodixanol impurity G according to claim 1, wherein: The synthesis method of the compound of formula 2 is as follows: using ethylene glycol methyl ether as a solvent, sodium methoxide as a nitrogen alkylating agent and the compound of formula 1 to react, and then adjusting the acid, concentrating, dissolving, decolorizing, desalting with resin, concentrating and drying to obtain the compound.

3. A method for preparing iodixanol impurity G according to claim 1, characterized in that: The synthesis method of the compound of formula 3 is as follows: a strong base, water and the compound of formula 2 are heated to produce a cyclization reaction, and the reaction is concentrated, desalted with methanol, dissolved, desalted with resin, re-concentrated, slurried with methanol, filtered and dried, acylated, and alcoholysed to obtain the compound.

4. A method for preparing iodixanol impurity G according to claim 3, characterized in that: The cyclization reaction temperature is 70-80° C., and the reaction time is 16 to 24 hours.

5. A method for preparing iodixanol impurity G according to claim 3, characterized in that: The temperature of the methanol desalination is -5 to 5°C.

6. The method for preparing the iodixanol impurity G according to claim 3, wherein: The amount of methanol in the slurry is 10 to 20 times the mass of the compound of formula 2.

7. The method for preparing the iodixanol impurity G according to claim 1, wherein: The synthesis method of the compound of formula 5 is as follows: after dissolving purified water, caustic soda flakes and the compound of formula 1, react with the compound of formula 4 under the protection of boric acid, adjust the acid, pass through a column, collect the corresponding fractions, concentrate under reduced pressure until a large amount of solid precipitates, filter, and dry to obtain a filter cake.

8. A method for preparing iodixanol impurity G according to claim 8, characterized in that: The reaction temperature of the compound of formula 1 and the compound of formula 4 is 0-10°C.

9. The method for preparing the iodixanol impurity G according to claim 8, wherein: The compound of formula 4 is 0.25 to 0.75 equivalent of the compound of formula 1.

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