CN116063195A

CN116063195A - Preparation method of iopamidol intermediate iodide

Info

Publication number: CN116063195A
Application number: CN202310021939.5A
Authority: CN
Inventors: 岳永力; 沈艳阳; 饶经纬; 顾建军; 张建; 杨冰
Original assignee: Anqing Langkun Pharmaceutical Co ltd
Current assignee: Anqing Langkun Pharmaceutical Co ltd
Priority date: 2023-01-07
Filing date: 2023-01-07
Publication date: 2023-05-05

Abstract

The invention provides a preparation method of iodides N, N-bis (1, 3-dihydroxyl-2-propyl) -5-amino-2, 4, 6-tri-iodo isophthalamide, which takes 5-amino-2, 4, 6-tri-iodo isophthaloyl chloride as a raw material, reacts with serinol in an organic solvent, and takes inorganic alkali solution as an acid-binding agent, so as to obtain iodides as key intermediates; the iodide prepared by the method has high yield and good purity. The reaction is easy to operate, the post-treatment is convenient, the reaction is safe, the environment is protected, and the method is suitable for large-scale industrial production.

Description

Preparation method of iopamidol intermediate iodide

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of an iodide of a medical intermediate N, N-bis (1, 3-dihydroxyl-2-propyl) -5-amino-2, 4, 6-tri-iodo-isophthalamide.

Background

N, N-bis (1, 3-dihydroxy-2-propyl) -5-amino-2, 4, 6-tri-iodo isophthalamide (CAS: 60166-98-5) is an important intermediate in the preparation of the contrast agent iopamidol. At present, 5-amino-2, 4, 6-diiodoisophthaloyl chloride is generally used as a raw material for preparation, for example, international patent publication number WO2018104228A1, which reacts with 5-amino-2, 4, 6-diiodoisophthaloyl chloride by high equivalent ratio, and the prepared iodides of iopamidol are lower in yield, which is only about 40%. Chinese patent CN105461581A reports a method for preparing iopamidol iodide under the condition of N, N-dimethylacetamide by using triethylamine as an acid-binding agent and 5-amino-2, 4, 6-diiodoisophthaloyl chloride and serinol, wherein the method has higher yield, but a large amount of triethylamine acid-binding agent and organic solvent N, N-dimethylacetamide are used in the reaction, the organic acid-binding agent is difficult to recycle, has stronger pungent taste, is not environment-friendly, and has higher preparation cost.

Disclosure of Invention

In view of the above, the present invention provides a method for preparing iopamidol iodide. The method takes 5-amino-2, 4, 6-triiodo isophthaloyl chloride as a raw material, reacts with serinol in an organic solvent, and takes inorganic alkali solution as an acid binding agent. The iodide prepared by the method has high yield and good purity. The reaction is easy to operate, the post-treatment is convenient, the reaction is safe, the environment is protected, and the method is suitable for large-scale industrial production.

Specifically, the above object is achieved by the following technical routes;

a preparation method of iodides of iopamidol intermediates comprises the following specific steps:

step 1: dissolving 5-amino-2, 4, 6-triiodo isophthaloyl chloride serving as a raw material in an organic solvent (I), cooling to 0-10 ℃, then adding serinol, stirring for 30 minutes, dropwise adding an inorganic alkali aqueous solution (II) serving as an acid binding agent, heating to 25-35 ℃, and carrying out heat preservation stirring reaction;

step 2: TLC detection, namely after the reaction of the raw materials is completed, regulating the pH value of the solution by using inorganic acid (III), stirring for 10-30 minutes after the completion of the regulation, concentrating and evaporating the solution at 90-110 ℃ under reduced pressure, then adding the mixed solution, cooling to 0-10 ℃, stirring for 4-8 hours, carrying out suction filtration, washing a filter cake by using a little of the mixed solution, and drying to obtain a white solid, thus obtaining the iodides N, N-bis (1, 3-dihydroxy-2-propyl) -5-amino-2, 4, 6-tri-iodo isophthalamide serving as an iodides intermediate; the above mixed solution is obtained by mixing water and an organic solvent (IV).

Preferably, the organic solvent (I) for dissolving the raw material 5-amino-2, 4, 6-diiodoisophthaloyl chloride may be any of N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, and preferably N, N-dimethylacetamide. The volume mass ratio of the organic solvent (I) to the raw material 5-amino-2, 4, 6-triiodo isophthaloyl chloride is 0.8-2:1, preferably 1-1.68:1, the volume-mass ratio unit is ml/g.

Preferably, the molar ratio of the raw material serinol to the 5-amino-2, 4, 6-triiodo isophthaloyl chloride is 2-5:1, preferably 2.4-3.96:1.

preferably, the inorganic alkaline aqueous solution (II) used as the acid-binding agent may be any one of sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, potassium carbonate solution, sodium bicarbonate solution, potassium bicarbonate solution, preferably sodium hydroxide solution; the inorganic alkaline solution (II) is used in a mass concentration of 5% to a saturation concentration, and the mass concentration of sodium hydroxide is preferably 20 to 35%.

Preferably, the inorganic acid (III) used for adjusting the pH of the solution is one of hydrochloric acid, sulfuric acid and phosphoric acid, and concentrated hydrochloric acid (37% by mass) is preferably used, and the pH of the solution after adjustment is between 5 and 9, preferably between 6.5 and 6.9.

Preferably, in the mixed solution, the volume ratio of water to the organic solvent (IV) is 1:4-4:1; the organic solvent (IV) can be one or more of methanol, ethanol, isopropanol, n-propanol, acetonitrile and acetone, preferably ethanol. The mixed solution is further preferably obtained by mixing ethanol and water in equal volumes.

Preferably, the drying temperature in the step 2 is 60-70 ℃, and the drying mode is reduced pressure or vacuum drying.

In practice, 5-amino-2, 4, 6-diiodoisophthaloyl chloride may be prepared by methods conventional in the art, or as a conventional commercially available product, provided that it has a purity of > 99%, may be used as a starting material for the reaction schemes of the present application.

The reaction equation involved in the above reaction scheme is as follows:

compared with the current method for preparing iopamidol iodide, the method has the following beneficial effects:

1. the reaction route does not use an acid binding agent (compared with WO 2018/104228), and the yield is greatly improved.

2. Compared with the CN105461581A patent, the organic acid binding agent is free of obvious pungent smell, is environment-friendly and has little harm to human bodies and environment; meanwhile, the inorganic acid binding agent has low cost and is easier for industrialized application.

3. The method regulates acid after the reaction is finished, and the generated salt is sodium chloride, potassium chloride and the like, so that the method is environment-friendly.

Drawings

FIG. 1 is a high performance liquid chromatogram of example 1.

FIG. 2 is a high performance liquid chromatogram of example 2.

FIG. 3 is a high performance liquid chromatogram of example 3.

FIG. 4 is a high performance liquid chromatogram of example 4.

FIG. 5 example 5 high performance liquid chromatogram.

Detailed Description

Unless otherwise indicated, the raw materials and reagents used in the following examples were all commercially available.

The 5-amino-2, 4, 6-triiodoisophthaloyl chloride was purchased from Jiangxi Siteli Co., ltd, with a purity of >98%. Serinol was purchased from Shanghai Michelin Biochemical technologies Co.

Example 1

1) 50mLN, N-Dimethylacetamide (DMAC), 29.8g (0.05 mol) of 5-amino-2, 4, 6-triiodoisophthaloyl chloride, stirring and dissolving, cooling to 5 ℃, slowly adding 18g (0.198 mol) of serinol, stirring (100 rpm, the same applies hereinafter) for 30 minutes, slowly adding 26.7g (containing 8.0g and 0.20 mol) of sodium hydroxide solution with the mass fraction of 30% dropwise, and completing the dropwise addition for about 10 minutes; after the addition, the temperature was raised to 35℃and after 2 hours TLC detection (n-hexane/ethyl acetate=5/1) the reaction was completed and the reaction was terminated.

2) The pH of the solution was adjusted to 6.5 with concentrated hydrochloric acid (37% by mass, the same applies hereinafter), then the solution was removed by concentrating under reduced pressure at 100 ℃ and 100ml of a mixed solution (obtained by mixing ethanol with water in equal volume) was added, after stirring for 1 hour, cooled to 5 ℃ and stirred at a constant temperature for crystallization for 6 hours, suction filtration, forced air drying of the cake at 65 ℃ for 8 hours, and stopping drying to obtain 29.8g of an off-white solid, which was confirmed to be iodipanol iodide, N, N-bis (1, 3-dihydroxy-2-propyl) -5-amino-2, 4, 6-tri-iodo isophthalamide by calculation with a yield of 84.4% (molar yield calculated as 5-amino-2, 4, 6-tri-iodo isophthaloyl chloride, the same applies hereinafter) and a purity of 92.64%, as shown in FIG. 1.

The liquid phase detection method according to this embodiment is as follows: using an agilent tcc18 liquid chromatography column (250 x 4.6nm x 5 um); flow rate: 1.0mL/min; column temperature: 30 ℃; wavelength: 240nm; mobile phase: a: methanol; b: phosphoric acid aqueous solution (ph=2.75) -50% acetonitrile water=94: 6, gradient elution (the same method as the detection method in the following examples).

Example 2

1) 50ml of DMAC and 29.8g (0.05 mol) of 5-amino-2, 4, 6-triiodo isophthaloyl chloride are added into a 250ml reaction bottle, stirred and dissolved, cooled to 5 ℃, 16.4g (0.18 mol) of serinol is slowly added, stirred for 30 minutes, 24g (containing 7.2g and 0.18mol of sodium hydroxide) of 30 mass percent sodium hydroxide solution is slowly added dropwise, the temperature is raised to 35 ℃ after the addition, TLC detection is carried out after 2 hours (n-hexane/ethyl acetate=5/1, and the reaction is finished after the raw materials are reacted completely.

2) The pH of the solution is regulated to 6.7 by concentrated hydrochloric acid (37 mass percent, the same applies below), after the regulation is finished, the solution is removed by decompression concentration, 100ml of ethanol-water mixed solution (ethanol/water=1/1, volume ratio) is added, after stirring for 1h, the temperature is reduced to 5 ℃, stirring and crystallization are carried out for 6h under heat preservation, suction filtration and air blast drying of a filter cake at 65 ℃ are carried out for 8h, drying is stopped, and 30.1g of white-like solid lopacol iodide is obtained, the liquid chromatography is shown in figure 2, the yield is 85.3%, and the purity is 96.26%.

Example 3

1) 45ml of DMAC and 29.8g (0.05 mol) of 5-amino-2, 4, 6-triiodo isophthaloyl chloride are added into a 250ml reaction bottle, stirred and dissolved, cooled to 5 ℃, 16.4g (0.18 mol) of serinol is slowly added, stirred for 30 minutes, 24g (containing 7.2g and 0.18mol of sodium hydroxide) of 30 mass percent sodium hydroxide solution is slowly added dropwise, the temperature is raised to 30 ℃ after the addition, TLC detection is carried out after 2 hours (n-hexane/ethyl acetate=5/1, and the reaction is finished after the raw materials are reacted completely.

2) The pH value of the solution is regulated to 6.8 by concentrated hydrochloric acid, after the regulation is finished, the solution is removed by decompression concentration, 90ml of ethanol-water mixed solution (ethanol/water=1/1, volume ratio) is added, after stirring for 1h, the temperature is reduced to 5 ℃, the temperature is kept, stirring and crystallization are carried out for 7h, suction filtration is carried out, a filter cake is dried for 8h at 65 ℃ in a stock mode, drying is stopped, 30.6g of off-white solid lopamidol iodide is obtained, the liquid chromatogram is shown in figure 3, the yield is 86.7%, and the purity is 96.46%.

Example 4

1) To a 250ml reaction flask was added 36ml of DMAC,29.8g (0.05 mol) of 5-amino-2, 4, 6-triiodo isophthaloyl chloride, dissolved by stirring, cooled to 5℃and slowly added 13.7g (0.15 mol) of serinol, stirred for 30 minutes, slowly added dropwise 24g (containing 7.2g,0.18mol of sodium hydroxide) of 30% sodium hydroxide solution, and after addition, the temperature was raised to 30℃and after 2 hours TLC detection (n-hexane/ethyl acetate=5/1) the reaction was completed. 2) The pH value of the solution is regulated to 6.9 by concentrated hydrochloric acid, after the regulation is finished, the solution is removed by decompression concentration, 90ml of ethanol-water mixed solution (ethanol/water=1/1, volume ratio) is added, after stirring for 1h, the temperature is reduced to 5 ℃, the temperature is kept, stirring and crystallization are carried out for 8h, suction filtration is carried out, a filter cake is washed by a little ethanol-water mixed solution, the filter cake is dried by blowing at 70 ℃ for 10h, drying is stopped, 31.5g of off-white solid lopamidol iodide is obtained, the liquid chromatogram is shown in figure 4, the yield is 89.2%, and the purity is 97.09%.

Example 5

1) 30ml of DMAC and 29.8g (0.05 mol) of 5-amino-2, 4, 6-triiodo isophthaloyl chloride are added into a 250ml reaction bottle, stirred and dissolved, cooled to 5 ℃, 11.0g (0.12 mol) of serinol is slowly added, stirred for 30 minutes, 18.2g (containing 6.0g and 0.15mol of sodium hydroxide) of 33% sodium hydroxide solution is slowly added dropwise, the addition is completed, the temperature is raised to 30 ℃ and TLC detection is carried out after 2 hours (n-hexane/ethyl acetate=5/1, and the reaction is finished after the raw material reaction is completed. 2) The pH value of the solution is regulated to 6.6 by concentrated hydrochloric acid, after the regulation is finished, the solution is removed by decompression concentration, 85ml of ethanol-water mixed solution (ethanol/water=1/2, volume ratio) is added, after stirring for 1h, the temperature is reduced to 5 ℃, the temperature is kept, stirring and crystallization are carried out for 10h, suction filtration is carried out, a filter cake is washed by a little ethanol-water mixed solution, the filter cake is dried by blowing at 70 ℃ for 10h, drying is stopped, 32.2g of off-white solid lopamidol iodide is obtained, the liquid chromatogram is shown in figure 5, the yield is 91.2%, and the purity is 97.39%.

Claims

1. A preparation method of iodides of iopamidol intermediates comprises the following specific steps:

1) Dissolving 5-amino-2, 4, 6-triiodo isophthaloyl chloride in an organic solvent (I), adding serinol at the temperature of 0-10 ℃, stirring, then dropwise adding an inorganic alkali solution, heating to the temperature of 25-35 ℃, and carrying out heat preservation and stirring to react until the 5-amino-2, 4, 6-triiodo isophthaloyl chloride is reacted;

the organic solvent (I) is any one of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone;

the inorganic alkali solution is any one of sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, potassium carbonate solution, sodium bicarbonate solution and potassium bicarbonate solution;

2) Regulating the pH value of a reaction system to 5-9 by inorganic acid, stirring for reaction, concentrating at 90-110 ℃ under reduced pressure, adding a mixed solution, cooling to 0-10 ℃, stirring for reaction, performing suction filtration, taking a filter cake, washing by the mixed solution, and drying to obtain the lopamidol intermediate iodide;

the mixed solution is obtained by mixing water and an organic solvent (II), wherein the organic solvent (II) is one or more of methanol, ethanol, isopropanol, n-propanol, acetonitrile and acetone.

2. The method for preparing iodides as claimed in claim 1, wherein the volume mass ratio of the organic solvent (I) to the 5-amino-2, 4, 6-diiodoisophthaloyl chloride in the step 1) is 0.8-2:1, the volume-mass ratio unit is mL/g.

3. The process for the preparation of iodides as claimed in claim 1, characterized in that the molar ratio of serinol to 5-amino-2, 4, 6-triiodiisophthaloyl chloride in step 1) is between 2 and 5:1.

4. the method for preparing iodides as claimed in claim 1, wherein the concentration of said inorganic alkaline solution in step 1) is between 5% and saturated.

5. The method for producing iodides as claimed in claim 1, wherein the step 1) is to adjust the pH of the reaction system to 6.5-6.9 with an inorganic acid.

6. The method for preparing iodides as claimed in claim 1, wherein the inorganic acid in the step 2) is one of hydrochloric acid, sulfuric acid and phosphoric acid.

7. The method for preparing iodides as claimed in claim 1, wherein the volume ratio of water to organic solvent (II) in the mixed solution of step 2) is 1:4-4:1.

8. The method for preparing iodides as claimed in claim 1, wherein the drying temperature in the step 2) is 60-70 ℃, and the drying mode is reduced pressure drying or vacuum drying.

9. The method for preparing iodides as claimed in claim 4, wherein said inorganic alkaline solution in step 1) is sodium hydroxide solution with concentration of 20-35%.

10. The method for preparing iodides as claimed in claim 1, wherein the volume ratio of water to organic solvent (II) in the mixed solution in step 2) is 1:1.