Preparation method of iohexol
Through a new iodhellol preparation method, the problems of low purity and yield of iodhellol in the prior art are solved through specific reaction steps and reagent ratios, and the effects of high purity, high yield and short reaction time are achieved, and the application value of iodhellol is enhanced.
Patent Information
- Application Number
- CN202411732392.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-28
- Publication Date
- 2025-03-04
AI Technical Summary
The existing preparation methods for alkylation of iodhellol hydrolysate have problems such as low purity and yield, high total alkoxylation content and long synthesis time, which limits the application value of iodhellol.
After mixing the iodhellol hydrolysate, propylene glycol and sodium methanol solution, 3-chloro-1,2-propylene glycol and sodium iodide are added for reaction, followed by adding 3-chloro-1,2-propylene glycol and sodium methanol solution, and then separating to obtain iodhellol.
The excellent purity and yield of iodine hexol are achieved, the reaction time is shortened, and the method is suitable for industrial production, thereby improving the application value of iodine hexol.
Smart Images
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Abstract
Description
Technical Field
[0001] The present invention relates to the field of medicines, and in particular to a method for preparing iohexol. Background Art
[0002] Iohexol is commonly used in cardiovascular angiography, arterial angiography, urography, venography and CT enhanced examination. Due to its low toxicity and good tolerance, it is widely used in clinical practice and is a commonly used contrast agent. The structure of iohexol is as follows:
[0003]
[0004] In the existing preparation methods of iohexol, alkylation of iohexol hydrolysate to prepare iohexol is a common synthesis process of iohexol. However, the existing alkylation of iohexol hydrolysate to prepare iohexol still has many problems, such as low purity and yield of the prepared iohexol, high total alkoxylation impurity content and a long synthesis time, etc., which limits the application value of iohexol.
[0005] Therefore, there is a need in the art to develop a method for preparing iohexol with excellent purity, yield and ease of industrial production. Summary of the invention
[0006] The object of the present invention is to provide a method for preparing iohexol with excellent purity and yield and easy industrial production.
[0007] In a first aspect, the present invention provides a method for preparing iohexol, wherein the method comprises:
[0008]
[0009] (1) mixing iodixanol hydrolyzate, propylene glycol and a methanol solution of sodium methoxide, adding 3-chloro-1,2-propylene glycol and sodium iodide, reacting to obtain a reaction solution;
[0010] (2) adding 3-chloro-1,2-propanediol and a methanol solution of sodium methoxide to the reaction solution obtained in step (1), reacting the mixture, and then separating and obtaining iohexol.
[0011] Preferably, in the step (1), the mass volume ratio (g:ml) of the iodine hydrolyzate to the propylene glycol is 1:(1-2.5), preferably 1:(1.4-2.2), more preferably 1:(1.6-2.0), and most preferably 1:1.8.
[0012] Preferably, in the step (1), the mass ratio of the iohexol hydrolyzate to the sodium methoxide methanol solution is (3-5):1, preferably (3.5-4.5):1, more preferably (3.8-4.2):1, and optimally 4.0:1.
[0013] Preferably, in the step (1), the content of sodium methoxide in the sodium methoxide methanol solution is 20-40wt%, preferably 25-35wt%, more preferably 28-32wt%, and most preferably 30wt%.
[0014] Preferably, in the step (1), the mass ratio of the iodixanol hydrolyzate to the 3-chloro-1,2-propanediol is (6-8):1, preferably (6.3-7.5):1, more preferably (6.6-7.0):1, and optimally 6.8:1.
[0015] Preferably, in the step (1), the mass ratio of the iodine hexol hydrolyzate to the sodium iodide is (40-60):1, preferably (45-55):1, more preferably (48-52):1, and optimally 50:1.
[0016] Preferably, in step (1), the iohexol hydrolyzate is 140-160 parts by weight, preferably 145-155 parts by weight, more preferably 148-152 parts by weight, and most preferably 150 parts by weight.
[0017] Preferably, in step (1), the amount of propylene glycol is 250-290 parts by weight, preferably 260-280 parts by weight, more preferably 265-275 parts by weight, and most preferably 270 parts by weight.
[0018] Preferably, in step (1), the sodium methoxide methanol solution is 30-50 parts by weight, preferably 33-45 parts by weight, more preferably 36-40 parts by weight, and most preferably 38 parts by weight.
[0019] Preferably, in step (1), the amount of 3-chloro-1,2-propanediol is 18-26 parts by weight, preferably 20-25 parts by weight, more preferably 21-23 parts by weight, and most preferably 22.2 parts by weight.
[0020] Preferably, in step (1), the sodium iodide is 3-4 parts by weight, preferably 3.5-4.5 parts by weight, more preferably 3.8-4.2 parts by weight, and most preferably 3 parts by weight.
[0021] Preferably, in step (1), the mixing temperature is 35-45°C, more preferably 38-42°C, and more preferably 40°C.
[0022] Preferably, in step (1), 3-chloro-1,2-propanediol and sodium iodide are added at 15-30°C (preferably 18-27°C, more preferably 20-25°C, and most preferably 23°C).
[0023] Preferably, in the step (1), after the mixing, the temperature of the mixture is adjusted to 15-30°C (preferably 18-27°C, more preferably 20-25°C, and most preferably 23°C), and then 3-chloro-1,2-propanediol and sodium iodide are added.
[0024] Preferably, in step (1), the reaction temperature is 15-30°C, preferably 18-27°C, more preferably 20-25°C, and most preferably 23°C.
[0025] Preferably, in step (1), the reaction time is 3-5 h, preferably 3.5-4.5 h, more preferably 3.8-4.2 h, and most preferably 4 h.
[0026] Preferably, the mass ratio of the iodixanol hydrolyzate in step (1) to the 3-chloro-1,2-propanediol in step (2) is (15-30):1, preferably (20-25):1, more preferably (22-24):1, and optimally 22.7:1.
[0027] Preferably, the mass ratio of the iodixanol hydrolyzate in step (1) to the sodium methoxide methanol solution in step (2) is (5-15):1, preferably (6-10):1, more preferably (7-9):1, and most preferably 8.3:1.
[0028] Preferably, in step (2), the amount of 3-chloro-1,2-propanediol is 5-8 parts by weight, preferably 6-7 parts by weight, more preferably 6.4-6.8 parts by weight, and most preferably 6.6 parts by weight.
[0029] Preferably, in step (2), the sodium methoxide methanol solution is 14-22 parts by weight, preferably 16-20 parts by weight, more preferably 17-19 parts by weight, and most preferably 18 parts by weight.
[0030] Preferably, in the step (2), the content of sodium methoxide in the sodium methoxide methanol solution is 20-40wt%, preferably 25-35wt%, more preferably 28-32wt%, and most preferably 30wt%.
[0031] Preferably, in step (2), the reaction temperature is 15-30°C, preferably 18-27°C, more preferably 20-25°C, and most preferably 23°C.
[0032] Preferably, in step (2), the reaction time is 5-7 h, more preferably 5.5-6.5 h, more preferably 5.8-6.2 h, and most preferably 6 h.
[0033] Preferably, in step (2), the separation comprises the following steps:
[0034] After the pH of the reaction solution after the reaction in step (2) is adjusted to 2-3, water is added and evaporated until no fraction is distilled out, and then water is added and stirred to dissolve to obtain a crude iohexol solution, which is successively purified by column purification using Amberlite XAD1600 macroporous resin, Amberlite FPC11Na ion exchange resin and Amberlite FPA91Cl ion exchange resin, and then rotary vacuum evaporation is performed to obtain a crude iohexol product, which is then recrystallized using ethanol to obtain iohexol.
[0035] Preferably, the pH of the reaction solution after the reaction in step (2) is adjusted with concentrated hydrochloric acid.
[0036] Preferably, the pH of the reaction solution after the reaction in step (2) is adjusted to 2.3-2.7, preferably 2.5.
[0037] Preferably, the step of adding water and distilling until no fraction is distilled out is repeated 3 times.
[0038] Preferably, the Amberlite XAD1600 macroporous resin is eluted with aqueous methanol.
[0039] Preferably, the volume fraction of methanol in the methanol aqueous solution is 10-30%, preferably 15-25%, more preferably 18-22%, and most preferably 20%.
[0040] Preferably, the Amberlite FPC11Na ion exchange resin is eluted with water.
[0041] Preferably, the Amberlite FPA91Cl ion exchange resin is eluted with water.
[0042] Preferably, the water comprises purified water.
[0043] Preferably, the ethanol recrystallization is performed once.
[0044] Preferably, the preparation method of iohexol comprises:
[0045] In a three-necked reaction bottle, 150 g of iodine hydrolyzate, 270 ml of propylene glycol and 38 g of 30 wt% sodium methoxide methanol solution were added, heated to 40 ° C, stirred and dissolved, then cooled to 23 ° C, 22.2 g of 3-chloro-1,2-propylene glycol and 3 g of sodium iodide were added, stirred at 23 ° C for 4 h, and then 6.6 g of 3-chloro-1,2-propylene glycol and 18 g of 30 wt% sodium methoxide methanol solution were added. After stirring at 23 ° C for 6 h, the pH of the reaction solution was adjusted to 2.5 with concentrated hydrochloric acid, 200 ml of water was added and evaporated until no fraction was evaporated, and then 200 mL of water was added and stirred to obtain a crude iodine solution, which was successively treated with Amberlite XAD1600 macroporous resin, AmberliteFPC11Na ion exchange resin and Amberlite After column purification with FPA91Cl ion exchange resin, crude iohexol was obtained by rotary evaporation under reduced pressure, and then recrystallized once with ethanol to obtain iohexol.
[0046] Preferably, the purity of the prepared iohexol is 99.6-99.9%, more preferably 99.7-99.9%, and more preferably 99.7-99.8%.
[0047] Preferably, the yield of the prepared iohexol is 99.5-99.9%, more preferably 99.5-99.6%.
[0048] Preferably, the total alkoxylated impurity content of the prepared iohexol is less than 0.2%, preferably less than 0.15%.
[0049] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. DETAILED DESCRIPTION
[0050] The present invention develops a method for preparing iohexol, which comprises mixing iohexol hydrolyzate, propylene glycol and a sodium methoxide methanol solution, adding 3-chloro-1,2-propylene glycol and sodium iodide, reacting to obtain a reaction solution, then adding 3-chloro-1,2-propylene glycol and a sodium methoxide methanol solution, reacting, and separating to obtain iohexol. The iohexol prepared by the method of the present invention has excellent purity and yield, and a short reaction time, which is conducive to industrial production, thereby improving the application value of iohexol.
[0051] the term
[0052] As used herein, the terms "include", "comprises", and "comprising" are used interchangeably, and include not only open definitions, but also semi-closed and closed definitions. In other words, the terms include "consisting of", "consisting essentially of".
[0053] As used herein, the structure of iohexol is as follows:
[0054]
[0055] As used herein, the structure of iohexol hydrolysate is as follows:
[0056]
[0057] As used herein, propylene glycol is also known as 1,2-propylene glycol.
[0058] As used herein, "wt %" refers to weight percentage, for example, 30 wt % sodium methoxide methanol solution means that the weight percentage of sodium methoxide in the sodium methoxide methanol solution is 30%, and so on.
[0059] As used herein, "v / v%" refers to volume percentage. For example, 20 v / v% methanol aqueous solution means that the volume percentage of methanol in the methanol aqueous solution is 20%, and so on.
[0060] method
[0061] The present invention provides a method for preparing iohexol, wherein the method comprises:
[0062]
[0063] (1) mixing iodixanol hydrolyzate, propylene glycol and a methanol solution of sodium methoxide, adding 3-chloro-1,2-propylene glycol and sodium iodide, reacting to obtain a reaction solution;
[0064] (2) adding 3-chloro-1,2-propanediol and a methanol solution of sodium methoxide to the reaction solution obtained in step (1), reacting the mixture, and then separating and obtaining iohexol.
[0065] Specifically, the preparation method of iohexol described in the present invention is as described above in the first aspect of the present invention.
[0066] The main excellent technical effects of the present invention include:
[0067] The invention develops a method for preparing iohexol. The iohexol prepared by the method has excellent purity and yield, and the reaction time is short, which is conducive to industrial production, thereby improving the application value of iohexol.
[0068] The present invention is further described below in conjunction with specific examples. It should be understood that the following specific examples are based on the technical solution and provide detailed implementation methods and specific operation processes, but the protection scope of the present invention is not limited to these examples.
[0069] Example 1
[0070] Preparation of iohexol:
[0071]
[0072] In a three-necked reaction bottle, 150 g of iodine hydrolyzate, 270 ml of propylene glycol and 38 g of 30 wt% sodium methoxide methanol solution were added, heated to 40 ° C, stirred and dissolved, then cooled to 23 ° C, 22.2 g of 3-chloro-1,2-propylene glycol and 3 g of sodium iodide were added, stirred at 23 ° C for 4 h, and then 6.6 g of 3-chloro-1,2-propylene glycol and 18 g of 30 wt% sodium methoxide methanol solution were added. After stirring at 23 ° C for 6 h, the pH of the reaction solution was adjusted to 2.5 with concentrated hydrochloric acid, 200 ml of water was added and evaporated until no fraction was evaporated (the operation of adding water and distilling was repeated 3 times), and then 200 mL of water was added and stirred to obtain a crude iodine solution, which was successively eluted with Amberlite XAD1600 macroporous resin (eluted with 20 v / v% methanol aqueous solution), Amberlite FPC11Na ion exchange resin (eluted with purified water) and Amberlite After column purification with FPA91Cl ion exchange resin (eluted with purified water), crude iohexol was obtained by rotary vacuum evaporation, which was recrystallized once with ethanol to obtain pure iohexol. The purity of the pure iohexol was 99.73%, the yield was 95.32%, and the total alkoxylated impurity content was 0.13%.
[0073] Comparative Example 1
[0074] Preparation of iohexol:
[0075]
[0076] In a three-necked reaction bottle, 150 g of iodine hydrolyzate, 270 ml of propylene glycol and 38 g of 30 wt% sodium methoxide methanol solution were added, heated to 40 ° C and stirred to dissolve, then cooled to 23 ° C, 22.2 g of 3-chloro-1,2-propylene glycol and 3 g of sodium iodide were added, and stirred at 23 ° C for 28 h. The pH of the reaction solution was adjusted to 2.5 with concentrated hydrochloric acid, 200 ml of water was added and evaporated until no fraction was distilled out (the operation of adding water and distilling was repeated 3 times), and then 200 mL of water was added and stirred to dissolve to obtain a crude iodine solution, and Amberlite XAD1600 macroporous resin (eluted with 20 v / v% methanol aqueous solution), Amberlite FPC11Na ion exchange resin (eluted with purified water) and Amberlite After column purification with FPA91Cl ion exchange resin (eluted with purified water), crude iohexol was obtained by rotary vacuum evaporation, which was recrystallized once with ethanol to obtain pure iohexol. The purity of the pure iohexol was 98.14%, the yield was 86.06%, and the total alkoxylated impurity content was 0.65%.
[0077] Comparative Example 2
[0078] Preparation of iohexol:
[0079]
[0080] 150g of iodine hydrolyzate, 270ml of propylene glycol and 38g of 30wt% sodium methoxide methanol solution were added to a three-necked reaction bottle, heated to 40°C and stirred to dissolve, then cooled to 23°C, 22.2g of 3-chloro-1,2-propylene glycol was added, stirred at 23°C for 4h, 6.6g of 3-chloro-1,2-propylene glycol and 18g of 30wt% sodium methoxide methanol solution were added, and stirring was continued at 23°C for 36h, the pH of the reaction solution was adjusted to 2.5 with concentrated hydrochloric acid, 200ml of water was added and evaporated until no fraction was evaporated (the operation of adding water and distilling was repeated 3 times), and then 200mL of water was added and stirred to dissolve to obtain a crude iodine solution, which was successively eluted with Amberlite XAD1600 macroporous resin (20v / v% methanol aqueous solution), Amberlite After column purification with FPC11Na ion exchange resin (eluted with purified water) and AmberliteFPA91Cl ion exchange resin (eluted with purified water), crude iohexol was obtained by rotary vacuum evaporation, which was then recrystallized once with ethanol to obtain pure iohexol. The purity of the pure iohexol was determined to be 97.65%, the yield was 84.37%, and the total alkoxylated impurity content was 0.73%.
[0081] The above is an implementation scheme of the present invention designed for a case. It should be pointed out that for ordinary technicians in this technical field, several improvements can be made without departing from the principle of the present invention, and these improvements should also be regarded as the scope of protection of the present invention.
Claims
1. A method for preparing iohexol, characterized in that: The method includes: (1) mixing iodixanol hydrolyzate, propylene glycol and a methanol solution of sodium methoxide, adding 3-chloro-1,2-propylene glycol and sodium iodide, reacting to obtain a reaction solution; (2) adding 3-chloro-1,2-propanediol and a methanol solution of sodium methoxide to the reaction solution obtained in step (1), reacting the mixture, and then separating and obtaining iohexol.
2. The method according to claim 1, characterized in that In the step (1), the mass volume ratio (g:ml) of the iohexol hydrolyzate to the propylene glycol is 1:(1-2.5), preferably 1:(1.4-2.2), more preferably 1:(1.6-2.0), and most preferably 1:1.8; In the step (1), the mass ratio of the iohexol hydrolyzate to the sodium methoxide methanol solution is (3-5):1, preferably (3.5-4.5):1, more preferably (3.8-4.2):1, and most preferably 4.0:1; In the step (1), the mass ratio of the iohexol hydrolyzate to the 3-chloro-1,2-propanediol is (6-8):1, preferably (6.3-7.5):1, more preferably (6.6-7.0):1, and most preferably 6.8:1; and In the step (1), the mass ratio of the iodine hexol hydrolyzate to the sodium iodide is (40-60):1, preferably (45-55):1, more preferably (48-52):1, and optimally 50:
1.
3. The method according to claim 2, characterized in that In the step (1), the content of sodium methoxide in the sodium methoxide methanol solution is 20-40wt%, preferably 25-35wt%, more preferably 28-32wt%, and most preferably 30wt%.
4. The method according to claim 1, characterized in that In the step (1), the reaction temperature is 15-30°C, preferably 18-27°C, more preferably 20-25°C, and most preferably 23°C.
5. The method according to claim 1, characterized in that In the step (1), the reaction time is 3-5 h, preferably 3.5-4.5 h, more preferably 3.8-4.2 h, and most preferably 4 h.
6. The method according to claim 1, characterized in that The mass ratio of the iohexol hydrolyzate in step (1) to the 3-chloro-1,2-propanediol in step (2) is (15-30):1, preferably (20-25):1, more preferably (22-24):1, and most preferably 22.7:1; and The mass ratio of the iodixanol hydrolyzate in step (1) to the sodium methoxide methanol solution in step (2) is (5-15):1, preferably (6-10):1, more preferably (7-9):1, and most preferably 8.3:
1.
7. The method according to claim 1, characterized in that In the step (2), the reaction temperature is 15-30°C, preferably 18-27°C, more preferably 20-25°C, and most preferably 23°C.
8. The method according to claim 1, characterized in that In the step (2), the reaction time is 5-7 h, preferably 5.5-6.5 h, more preferably 5.8-6.2 h, and most preferably 6 h.
9. The method according to claim 1, characterized in that In the step (2), the separation comprises the following steps: After the pH of the reaction solution after the reaction in step (2) is adjusted to 2-3, water is added and evaporated until no fraction is distilled out, and then water is added and stirred to dissolve to obtain a crude iohexol solution, which is successively purified by column purification using Amberlite XAD1600 macroporous resin, Amberlite FPC11Na ion exchange resin and Amberlite FPA91Cl ion exchange resin, and then rotary reduced pressure evaporation is performed to obtain a crude iohexol product, which is then recrystallized using ethanol to obtain iohexol.
10. The method according to claim 1, characterized in that The preparation method of the iohexol comprises: In a three-necked reaction bottle, 150 g of iodine hydrolyzate, 270 ml of propylene glycol and 38 g of 30 wt% sodium methoxide methanol solution were added, heated to 40 ° C, stirred and dissolved, then cooled to 23 ° C, 22.2 g of 3-chloro-1,2-propylene glycol and 3 g of sodium iodide were added, stirred at 23 ° C for 4 h, and then 6.6 g of 3-chloro-1,2-propylene glycol and 18 g of 30 wt% sodium methoxide methanol solution were added. After stirring at 23 ° C for 6 h, the pH of the reaction solution was adjusted to 2.5 with concentrated hydrochloric acid, 200 ml of water was added and evaporated until no fraction was evaporated, and then 200 mL of water was added and stirred to obtain a crude iodine solution, which was successively treated with Amberlite XAD1600 macroporous resin, AmberliteFPC11Na ion exchange resin and Amberlite After column purification with FPA91Cl ion exchange resin, crude iohexol was obtained by rotary evaporation under reduced pressure, and then recrystallized once with ethanol to obtain iohexol.