Industrial preparation method of iodixanol

Abstract

The present invention relates to the field of pharmaceutical chemical technology, and in particular to a method for industrial preparation of iodixanol, wherein a crude iodixanol product is synthesized by a dimerization reaction of 5-acetylamino-N, N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide (compound of formula II) under the action of a catalyst, and then ethanol is used for recrystallization to obtain a finished iodixanol product. The process route of the method is simple, and impurity generation can be effectively reduced, reaction conversion efficiency can be greatly improved, reaction substrate can be completely converted, and yield is greatly improved compared to the prior art, and reaction liquid HPLC purity is up to more than 70%, which is very suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical industry, and specifically relates to an industrial preparation method of iodixanol. Background Art

[0002] Iodixonal is a non-ionic X-ray contrast agent developed by Nycomed, Norway. Its chemical name is 5,5'-((2-hydroxy-1,3-propane)bis(acetimido))bis(N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarbamide. Its molecular structure is shown in Formula I:

[0003]

[0004] Some studies have shown that iodixanol can effectively reduce the occurrence of complications more effectively than other contrast agents and is safer and more effective to use. Iodixanol is directly administered by injection and the dosage is high, so this places high demands on the quality of iodixanol APIs, so it is necessary to focus on the production and purification process of iodixanol.

[0005] The existing iodixanol production is mainly through the dimerization synthesis of 5-acetylamino-N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodo-isophthalamide (compound of formula II), but some by-products and impurities are still generated. US2012184773A1 discloses that the compound of formula II uses dimethylacetamide (DMAc) and water as a mixed solvent. Under the condition of adding potassium iodide, epichlorohydrin dimerizes to form iodixanol, and iodixanol and impurity G are also generated. The yield of iodixanol is also low, only 52%; and the reaction substrate compound of formula II is still not completely reacted after 45 hours, and the residual amount is more than 38%. The structural formulas of the compound of formula II, iodixanol, and impurity G are as follows:

[0006]

[0007] CA2710618A1 discloses that the compound of formula II is dimerized into iodixanol by epichlorohydrin with methanol as solvent, and byproducts iohexanol, N-acetyl cyclized iodixanol and iopentol are also generated. The compound of formula II also fails to react completely, and the residual amount of the reaction substrate compound of formula II is still more than 46% after 48 hours of reaction. The structural formulas of the compound of formula II, iohexanol, N-acetyl cyclized iodixanol and iopentol are as follows:

[0008]

[0009] Therefore, it is necessary to optimize the production process of iodixanol. Summary of the invention

[0010] In order to solve the problems existing in the prior art, the present invention provides an industrial preparation method of iodixanol, wherein the preparation method comprises: reacting a compound of formula II with epichlorohydrin in the presence of a catalyst to produce a dimerization product. The reaction formula is as follows:

[0011]

[0012] Wherein, the catalyst is one of aluminum chloride, ferric chloride and zinc chloride, preferably zinc chloride.

[0013] The molar ratio of the compound of formula II to the catalyst is 1:(0.001-0.5), more preferably, the molar ratio of the compound of formula II to the catalyst is 1:(0.01-0.2), further preferably, the molar ratio of the compound of formula II to the catalyst is 1:(0.02-0.1), and most preferably, the molar ratio of the compound of formula II to the catalyst is 1:0.05.

[0014] The molar ratio of the compound of formula II to epichlorohydrin is 1:(0.1-0.6), preferably, the molar ratio of the compound of formula II to epichlorohydrin is 1:(0.3-0.5), and most preferably, the molar ratio of the compound of formula II to epichlorohydrin is 1:0.5.

[0015] The reaction solvent is selected from at least one of water, dimethylformamide (DMF), acetonitrile and ethanol, preferably DMF.

[0016] The reaction temperature is controlled at 5-30°C, more preferably at room temperature.

[0017] The reaction time is controlled within a range of 0.5-10 hours, more preferably 2-5 hours.

[0018] The preparation method further comprises the step of adding an alkali metal base, wherein the alkali metal base is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate, and more preferably, the alkali metal base is selected from sodium hydroxide and potassium hydroxide.

[0019] Preferably, the alkali metal base is in the form of a solution. Preferably, the concentration of the alkali metal base solution is 1%-30% w / v, most preferably 25% w / v.

[0020] Preferably, the pH of the reaction system is adjusted to 4-9, more preferably 6-7.

[0021] In a preferred technical scheme, the preparation method of the iodixanol is as follows: the compound of formula II reacts with epichlorohydrin in the presence of a catalyst, and after the reaction is completed, an alkali metal base is added to adjust the pH to prepare the crude iodixanol product, which is initially separated by a dynamic axial compression column, and then recrystallized using ethanol to obtain the finished iodixanol product.

[0022] Wherein, the catalyst is one of aluminum chloride, ferric chloride and zinc chloride, preferably zinc chloride.

[0023] The molar ratio of the compound of formula II to the catalyst is 1:(0.001-0.5), more preferably, the molar ratio of the compound of formula II to the catalyst is 1:(0.01-0.2), further preferably, the molar ratio of the compound of formula II to the catalyst is 1:(0.02-0.1), and most preferably, the molar ratio of the compound of formula II to the catalyst is 1:0.05.

[0024] The molar ratio of the compound of formula II to epichlorohydrin is 1:(0.1-0.6), preferably, the molar ratio of the compound of formula II to epichlorohydrin is 1:(0.3-0.5), and most preferably, the molar ratio of the compound of formula II to epichlorohydrin is 1:0.5.

[0025] The alkali metal base is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate, and more preferably, the alkali metal base is selected from sodium hydroxide and potassium hydroxide. Preferably, the alkali metal base is in the form of a solution. Preferably, the concentration of the alkali metal base solution is 1%-30% w / v, and most preferably 25% w / v.

[0026] Preferably, the pH of the reaction system is adjusted to 4-9, more preferably 6-7.

[0027] The reaction solvent is selected from water, dimethylformamide (DMF), acetonitrile, and ethanol, and more preferably DMF.

[0028] The reaction temperature is controlled at 5-30°C, more preferably at room temperature.

[0029] The reaction time is controlled within a range of 0.5-10 hours, more preferably 2-5 hours.

[0030] The technical solution of the present invention has the following beneficial effects:

[0031] The invention provides an industrial preparation method of iodixanol. Compared with the existing preparation method of iodixanol, the technical solution of the invention can effectively reduce the generation of impurities and greatly improve the reaction conversion efficiency. In addition, the technical solution of the invention uses zinc chloride as a catalyst, so that the reaction substrate is maximized, the reaction efficiency is significantly improved, and the HPLC purity of the reaction liquid is as high as more than 70%, which is very suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is the HPLC analysis spectrum of the iodixanol reaction solution prepared by the method described in Example 1. DETAILED DESCRIPTION

[0033] In order to better understand the technical solution of the present invention, the technical solution of the present invention is further described below in conjunction with specific embodiments. The embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0034] The following reaction solutions were respectively tested for the crude content of iodixanol by HPLC method. After the reaction solution was concentrated, it was dissolved in water-acetonitrile (30:70) with a concentration of 1 mg / mL. The injection volume was 10 μL each time. The chromatographic column used was Agilent Zorbax NH2 with a specification of 250 mm×4.6 mm, a particle size of 5 μm, a detection wavelength of 254 nm, a column temperature of 25°C, and gradient elution. The acetonitrile gradient of the elution mobile phase was reduced from 85% to 5% within 0 to 55 min, and the flow rate was 1.5 mL / min.

[0035] Example 1: Preparation of iodixanol

[0036] Epichlorohydrin (49.54 kg, 535.43 mol) was dissolved in 1000 kg of dimethylformamide in a 3000 L reactor, and the compound of formula II (800 kg, 1070.86 mol) and zinc chloride (7.3 kg, 53.543 mol) were added and dissolved under stirring, and reacted at room temperature for 5 hours, and 900 kg of potassium hydroxide solution (25% w / v) was added to adjust the pH to 6-7, and the mixture was stirred for 20 minutes under heat preservation. The HPLC purity of the reaction solution was 71.46%. The HPLC spectrum is shown in FIG. Figure 1 , the integral data is as follows:

[0037]

[0038] Those skilled in the art know that retention times 25.957-29.872 are all iodixanol peak positions. Therefore, to calculate the integral content of iodixanol in the reaction solution, the values ​​within the range of 25.957-29.872 should be added, that is, Figure 1In the experiment, the concentration of iodixanol accounts for 27.67%+43.79%=71.46%.

[0039] Example 2: Preparation of iodixanol

[0040] In a 2000ml reaction bottle, epichlorohydrin (33g, 0.36mol) was dissolved in 500g of dimethylformamide, and the compound of formula II (533g, 0.71mol) and aluminum chloride (4.74g, 0.0355mol) were added under stirring. The mixture was reacted at room temperature for 3 hours, and 600g of potassium hydroxide solution (25% w / v) was added to adjust the pH to 6-7. The mixture was stirred for 10 minutes at the temperature. The reaction solution had a HPLC purity of 68.59%.

[0041] Example 3: Preparation of iodixanol

[0042] In a 2000ml reaction bottle, epichlorohydrin (33g, 0.36mol) was dissolved in 500g of dimethylformamide, and the compound of formula II (533g, 0.71mol) and ferric chloride (5.76g, 0.0355mol) were added under stirring. The mixture was reacted at room temperature for 3 hours, and 600g of potassium hydroxide solution (25% w / v) was added to adjust the pH to 6-7. The mixture was stirred for 10 minutes at the temperature. The reaction solution had a HPLC purity of 69.34%.

[0043] Example 4: Preparation of iodixanol

[0044] In a 2000ml reaction bottle, add epichlorohydrin (33g, 0.36mol) to 500g of water, add the compound of formula II (533g, 0.71mol) and zinc chloride (4.84g, 0.0355mol) under stirring, react at room temperature for 4 hours, add 600g of potassium hydroxide solution (25% w / v) to adjust the pH to 6-7, keep warm and stir for 10 minutes, the reaction liquid HPLC purity is 63.92%.

[0045] Example 5: Preparation of iodixanol

[0046] In a 2000ml reaction bottle, add epichlorohydrin (33g, 0.36mol) to 500g of ethanol, add the compound of formula II (533g, 0.71mol) and zinc chloride (4.84g, 0.0355mol) under stirring, react at room temperature for 3 hours, add 600g of potassium hydroxide solution (25% w / v) to adjust the pH to 6-7, keep warm and stir for 10 minutes, the reaction liquid HPLC purity is 62.74%.

[0047] Example 6: Preparation of iodixanol

[0048] Epichlorohydrin (33 g, 0.36 mol) was added to 500 g of acetonitrile in a 2000 ml reaction bottle, and the compound of formula II (533 g, 0.71 mol) and zinc chloride (4.84 g, 0.0355 mol) were added under stirring. The mixture was reacted at room temperature for 3 hours, and 600 g of potassium hydroxide solution (25% w / v) was added to adjust the pH to 6-7. The mixture was stirred at the temperature for 10 minutes. The reaction solution had a HPLC purity of 65.71%.

Claims

1. An industrial preparation method of iodixanol, which is prepared by dimerization reaction of a compound of formula (II) with epichlorohydrin in the presence of a catalyst, and the reaction formula is as follows: The catalyst is one of aluminum chloride, ferric chloride and zinc chloride; The molar ratio of the compound of formula (II) to the catalyst is 1:0.05; The molar ratio of the compound of formula (II) to epichlorohydrin is 1:0.5; The reaction solvent is selected from at least one of water, dimethylformamide, acetonitrile and ethanol; The reaction temperature is room temperature, and the reaction time is 3-5 hours.

2. The preparation method according to claim 1, wherein the catalyst is zinc chloride.

3. The preparation method according to claim 1, wherein the solvent of the reaction is dimethylformamide.

4. The preparation method according to any one of claims 1 to 3, further comprising the step of adding alkali to adjust the pH to 6 to 7, wherein the alkali is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate.

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