阅读说明：本技术 一种制备碘佛醇的方法 (Method for preparing ioversol ) 是由 边奕澄 黄成伟 熊峰 时秋燕 魏菱 于 2021-10-09 设计创作，主要内容包括：本发明公开了一种药物碘佛醇的制备方法,属于医药中间体技术领域。从(5-羟基乙酰胺基)-N,N’-双(2,3-二羟丙基)-2,4,6-三碘-1,3-苯二甲酰胺(1)出发,经过丙酮叉保护得到中间体(2)；接着中间体(2)与氯乙醇发生取代反应得到中间体(3),最后中间体(3)脱丙酮叉保护反应得到碘佛醇。本发明通过不同层级的保护,即使强碱性条件也不产生重排异构体,避免了杂质II的生成,工艺重现性好,可顺利放大到公斤级反应规模。(The invention discloses a preparation method of a medicine ioversol, belonging to the technical field of medical intermediates. Starting from (5-hydroxyacetamido) -N, N' -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide (1), obtaining an intermediate (2) through acetonide protection; then the intermediate (2) and chloroethanol are subjected to substitution reaction to obtain an intermediate (3), and finally the intermediate (3) is subjected to deacetonylidene protection reaction to obtain ioversol. Through different levels of protection, the method does not produce rearrangement isomers even under strong alkaline conditions, avoids the generation of impurities II, has good process reproducibility, and can be smoothly amplified to kilogram-level reaction scale.)

1. The preparation method of ioversol is characterized in that the synthetic route is as follows:

the method comprises the following steps: starting from (5-hydroxyacetamido) -N, N' -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide (1), obtaining an intermediate (2) through acetonide protection; then the intermediate (2) and chloroethanol are subjected to substitution reaction to obtain an intermediate (3), and finally the intermediate (3) is subjected to deacetonylidene protection reaction to obtain ioversol.

2. The process for the preparation of ioversol according to claim 1, wherein: the first step is that (5-hydroxyacetamido) -N, N' -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide (1) reacts with acetonide and vinyl ether in sequence under an acidic condition to obtain an acetonide protected intermediate (2).

3. A process for the preparation of ioversol according to claim 2, wherein: in the first operation, the propylene glycol is selected from the group consisting of diacetone dimethyl acetal, diacetone diethyl acetal and diacetone isopropyl alcohol; the vinyl ether is selected from vinyl methyl ether or vinyl ethyl ether.

4. A process for the preparation of ioversol according to claim 2, wherein: in the first step of operation, the acid is p-toluenesulfonic acid or ammonium chloride; the solvent is selected from acetone, tetrahydrofuran or dichloromethane; the molar ratio of the (5-hydroxyacetamido) -N, N' -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide (1) to the acid is 1: 0.01-0.12.

5. A process for the preparation of ioversol according to claim 2, wherein: in the second step, the intermediate (2), chlorohydrin and alkali are reacted in an organic solvent to obtain an intermediate (3).

6. The process for the preparation of ioversol according to claim 5, wherein: in the second step, the organic solvent is selected from methanol, N-dimethylformamide, acetonitrile, isopropanol or any combination of the above solvents; the base is selected from cesium carbonate, dipotassium hydrogen phosphate, potassium tert-butoxide, potassium carbonate or sodium carbonate.

7. The process for the preparation of ioversol according to claim 5, wherein: in the second operation, the molar ratio of the intermediate (2), alkali and chloroethanol is 1: 1-3: 1-2.

8. A process for the preparation of ioversol according to claim 2, wherein: in the third step, the intermediate (3) and acid react in an organic solvent to obtain the ioversol (I).

9. A process for the preparation of ioversol according to claim 8, wherein: in the third operation, the organic solvent is selected from tetrahydrofuran, acetonitrile, methanol or any combination of the solvents; the acid is hydrochloric acid or glacial acetic acid.

10. A process for the preparation of ioversol according to claim 8, wherein: in the third operation, the molar ratio of the intermediate (3) to the acid is 1: 1-2.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of ioversol serving as a marketed medicine.

Background

Ioversol (ivoresol), an english name, is a new non-ionic contrast agent developed by wanlingke medicine limited (Mallinkrodt Medical Inc.), is approved by FDA in the united states for marketing in 1988, and is currently marketed in japan, england, france, china, etc. After the ioversol is injected, the X-ray is attenuated due to the high electric quantity, so that the vascular imaging of the route can be clear.

Ioversol chemical name is N, N' -bis (2, 3-dihydroxypropyl) -5- [ N- (2-hydroxyethyl) glycolylamino]-2,4, 6-triiodo-1, 3-benzenedicarboxamide, chemigationStructure is as

The preparation method of ioversol has more reports in documents. 5-amino-2, 4, 6-triiodoisotitanic acid is mostly used as a starting material to prepare ioversol through side chain substitution in sequence, and literature reports mostly focus on the adjustment of the method.

US4396598 discloses a process for preparing ioversol, which comprises using 5-amino-2, 4, 6-triiodoisotitanic acid as starting material, and performing acyl chlorination to substitute side chain at 1, 3-position (2, 3-dihydroxypropylamine), acetyl protection, acetoxyacetyl chloride and deacetylation protection, and finally substituting with chloroethanol to obtain ioversol finished product. The final step of the process reacts with chloroethanol to easily generate Smiles rearrangement to generate impurities IIImpurity II is difficult to remove in the finished product.

In the method for preparing ioversol reported in U.S. Pat. No. 5,5648536, acetoxyacetyl chloride is replaced by chloroacetyl chloride with better stability, and alkylation is still required in the last step of the process under alkaline conditions, so that the generation of impurity II is difficult to avoid.

Chinese patent CN187317 discloses another method for preparing ioversol, which adjusts the order of chlorine hydrolysis based on US5648536, but still it is difficult to avoid the generation of impurity II.

The currently disclosed methods for preparing ioversol cannot effectively avoid the generation of impurities II, and the prepared finished product can meet the medicinal requirements by multiple refining methods.

Therefore, the invention provides a novel preparation method of ioversol, and the route can remarkably reduce or avoid the generation of impurities II which are difficult to remove.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides the preparation method of ioversol, which has the advantages of simple and stable operation, easy separation of products in each step, high yield, environmental protection and suitability for industrial mass production.

The invention provides a preparation method of ioversol, which comprises the following synthetic route:

the method comprises the following steps: starting from (5-hydroxyacetamido) -N, N' -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide (1), obtaining an intermediate (2) through acetonide protection; then the intermediate (2) and chloroethanol are subjected to substitution reaction to obtain an intermediate (3), and finally the intermediate (3) is subjected to deacetonylidene protection reaction to obtain ioversol.

Further, the technical method provided by the invention comprises the following specific steps:

the first step is as follows: synthesis of intermediate (2)

Reacting (5-hydroxyacetamido) -N, N' -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide (1) with acetonide and vinyl ether in sequence under an acidic condition to obtain an acetonide protected intermediate (2).

Further, the propylene glycol is selected from the group consisting of acetonide, acetonide or acetonide isopropanol.

Further, the vinyl ether is selected from vinyl methyl ether or vinyl ethyl ether.

Further, the acid is p-toluenesulfonic acid or ammonium chloride.

Furthermore, the solvent is selected from acetone, tetrahydrofuran, dichloromethane and the like, mainly plays a role in dissolution, and has no obvious influence on reaction yield; the preferred solvent is dichloromethane.

Further, the molar ratio of the (5-hydroxyacetamido) -N, N' -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide (1) to the acid is 1: 0.01-0.12.

The second step is that: synthesis of intermediate (3)

And (3) reacting the intermediate (2), chloroethanol and alkali in an organic solvent to obtain an intermediate (3).

Further, the organic solvent is selected from methanol, N-dimethylformamide, acetonitrile, isopropanol or any combination of the above solvents, preferably N, N-dimethylformamide.

Further, the base is selected from cesium carbonate, dipotassium hydrogen phosphate, potassium tert-butoxide, potassium carbonate, sodium carbonate, and the like.

Further, the intermediate (2), the molar ratio of the base to the chloroethanol is 1: 1-3: 1-2.

The third step: synthesis of ioversol (I)

And (3) reacting the intermediate (3) with acid in an organic solvent to obtain ioversol (I).

Further, the organic solvent is selected from tetrahydrofuran, acetonitrile, methanol or any combination of the above solvents, preferably the solvent is methanol.

Further, the acid is hydrochloric acid or glacial acetic acid.

Further, the molar ratio of the intermediate (3) to the acid is 1: 1-2.

The invention has the beneficial effects

1) Through protection of different levels, rearrangement isomers are not generated even under strong alkaline conditions, impurity II is prevented from being generated, and the quality of products is improved;

2) the invention optimizes the preparation process, the reaction can be continuously carried out, the high-purity product can be obtained by methanol recrystallization in the final step, the operation of the post-treatment process is simple, the process reproducibility is good, and the method can be smoothly amplified to the kilogram-level reaction scale.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.

Example 1

The first step is as follows:

(5-Hydroxyacetamido) -N, N' -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide (1) (1.0g, 1.31mmol) and p-toluenesulfonic acid (2.26mg, 0.013mmol) were added to a solution of acetonide dimethyl ether (163.78mg, 1.57 mmol)/acetone (18mL), the reaction was refluxed for 5 hours and then cooled to 0-5 ℃, a solution of vinyl methyl ether (83mg, 1.44 mmol)/acetone (2mL) was slowly dropped into the reaction system, which was then stirred at room temperature for 18 hours, washed with an aqueous sodium bicarbonate solution, extracted with dichloromethane, and spin-dried to give intermediate 2(0.98g, yield: 84%).

The second step is that:

intermediate 2(0.71g, 0.79mmol), chlorohydrin (0.126g, 1.58mmol) and potassium carbonate (0.327g, 2.37mmol) were added to methanol (14mL), stirred at room temperature for 4 hours, added saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic layer was spin dried to give intermediate 3(0.74g) which was used directly in the next step;

the third step:

glacial acetic acid (0.094g, 1.57mmol) was added to a solution of intermediate 3(0.74g, 0.78mmol) in methanol (3.7ml) at 0-5 deg.C, stirred at room temperature for 2 hours, the solvent was spun off, and the crude product was recrystallized from methanol to yield ioversol (0.5g, 79% yield).¹H NMR(400MHz,DMSO-d₆):3.40-3.51(m,4H),3.57-3.71(m,4H),3.75(m,2H),3.79(m,2H),3.83(s,2H),3.96(m,2H),4.6-4.9(m,6H),8.4-8.6(d,2H).

Example 2

The first step is as follows:

(5-Hydroxyacetamido) -N, N' -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide (1) (100g, 131.05mmol) and ammonium chloride (83.9mg, 1.57mmol) were added to a solution of diacetone diethyl ether (20.79g, 157.26mmol) and tetrahydrofuran (1.8L), the reaction was refluxed and heated for 5 hours, then cooled to 0-5 ℃ and a vinyl ethyl ether (11.34g, 157.26 mmol)/tetrahydrofuran (0.2L) solution was slowly dropped into the reaction system, followed by stirring at room temperature for 18 hours, washing with an aqueous sodium bicarbonate solution, extraction with dichloromethane, and spin-drying to give intermediate 2(103.2g, yield: 86%).

The second step is that:

intermediate 2(74.37g, 81.25mmol), chlorohydrin (9.81g, 121.88mol) and cesium carbonate (52.94g, 162.5mmol) were added to N, N-dimethylformamide (1.5L), stirred at room temperature for 4 hours, added with saturated aqueous ammonium chloride solution, and extracted with dichloromethane. The organic layer was spin dried to give intermediate 3(78g) which was used directly in the next step;

the third step:

concentrated hydrochloric acid (6.77mL, 81.33mmol) was added to a solution of intermediate 3(78g, 81.3 mmol)/acetonitrile (390mL) at 0-5 deg.C, stirred for 2 hours at room temperature, the solvent was spun off, and the crude product was recrystallized from methanol to yield ioversol (53.2g, 81% yield).

Example 3

The first step is as follows:

adding (5-hydroxyacetamido) -N, N' -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide (1) (1kg, 1.31mol) and p-toluenesulfonic acid (2.71g, 15.73mmol) into a solution of diacetone isopropyl alcohol (252.02g, 1.57 mol)/dichloromethane (18L), heating under reflux for 5 hours, cooling to 0-5 ℃, slowly dropping a solution of vinyl methyl ether (83.72g, 1.44 mol)/dichloromethane (2L) into the reaction system, stirring at room temperature for 18 hours, adding an aqueous solution of sodium bicarbonate for washing, extracting with dichloromethane, and spin-drying to obtain 0.95kg of intermediate 2.

The second step is that:

intermediate 2(0.71kg, 787.78mmol), chlorohydrin (63.43g, 787.78mmol) and potassium tert-butoxide (88.9mmol, 787.78mmol) were added to acetonitrile (14L), stirred at room temperature for 4 hours, added saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic layer was spin dried to give intermediate 3(0.74kg) which was used directly in the next step;

the third step:

glacial acetic acid (70.51g, 1.17mol) was added to a solution of intermediate 3(0.74kg, 0.78 mol)/tetrahydrofuran (3.7L) at 0-5 deg.C, stirred at room temperature for 2 hours, the solvent was spun off, and the crude product was recrystallized from methanol to yield ioversol (0.51kg, yield 80.9%).

The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.